Considering patient perspectives in economic evaluations of health interventions

Frontiers in Public Health 01 frontiersin.org

Considering patient perspectives

in economic evaluations of health

interventions

RuiFu

1,2

, VivianNg

, MichaelLiu

, DavidWells

, EmreYurga

and

EricNauenberg

2,6

Department of Otolaryngology—Head & Neck Surgery, Sunnybrook Research Institute, University of

Toronto, Toronto, ON, Canada,

Institute of Health Policy, Management and Evaluation, University of

Toronto, Toronto, ON, Canada,

Roche Diagnostics, Laval, QC, Canada,

Harvard Medical School,

Harvard University, Boston, MA, United States,

The Canadian Agency for Drugs and Technologies in

Health (CADTH), Nanaimo, BC, Canada,

Ontario Ministry of Health, Toronto, ON, Canada

Current guidelines for evaluating the cost-eectiveness of health interventions

commonly recommend the use of a payer and/or a societal perspective. This

raises the concern that the resulting reimbursement decision may overlook the

full spectrum of impacts and equity considerations. In this paper, weargue that

a potential solution is to supplement a societal- or payer-perspective economic

evaluation with an additional evaluation accounting for exclusively the patient

perspective. We present ﬁve categories of health interventions for which a

patient-perspective analysis may be informative including those (1) that cross

the deﬁnitional boundary between drugs and non-drug technologies; (2) aect

patient adherence to protocol; (3) represent revolutionary treatments for genetic

disorders; (4) with an incremental cost-eectiveness ratio involving slightly less

eective, but substantially less costly, than the current standard; and (5) have been

previously approved for funding but now being targeted for potential delisting

or disinvestment. Real-world examples are discussed in detail. Lived experience

individuals were invited to provide vignettes. Discussions are provided regarding

how to incorporate patient inputs to improve patient-centered decision-making.

KEYWORDS

health economics, cost-eectiveness analysis, economic evaluations, patient-centered

care, patient preference

1. Introduction

Economic evaluations, as reviewed by Turner etal. in an earlier issue of Frontiers in Public

Health, refer to a type of analysis that simultaneously assesses the costs and eects of alternative

interventions to ensure value for resources expended from various perspectives (1). Although

there have been attempts to address equity considerations in cost-eectiveness analyses (CEAs)

through the development of distributional and extended cost-eectiveness methods, they stated

that “this is still an area that needs attention regarding practical implementation with regards to

informing resource allocation decisions in global health” (1). is shortfall emanates, in part,

from inadequate analysis of the burdens placed on individuals and families from the introduction

of new health interventions.

Commonly, only the societal and/or the payer perspective are recommended by health

technology assessment (HTA) agencies. At the national level, the latter is endorsed by countries

including Australia, the UK and Canada (2). Other countries (e.g., ailand) have

recommended a societal perspective while at least one—Norway—has limited it to exclude

OPEN ACCESS

EDITED BY

Hanadi Hamadi,

University of North Florida, UnitedStates

REVIEWED BY

Robert L. Lins,

Independent Researcher, Antwerp,

Belgium

Damilola Olajide, University of Nottingham,

UnitedKingdom

*CORRESPONDENCE

Eric Nauenberg

[email protected]

RECEIVED 26 April 2023

ACCEPTED 25 September 2023

PUBLISHED 09 October 2023

CITATION

Fu R, Ng V, Liu M, Wells D, Yurga E and

Nauenberg E (2023) Considering patient

perspectives in economic evaluations of health

interventions.

Front. Public Health 11:1212583.

doi: 10.3389/fpubh.2023.1212583

Nauenberg. This is an open-access article

distributed under the terms of the Creative

Commons Attribution License (CC BY). The

use, distribution or reproduction in other

forums is permitted, provided the original

author(s) and the copyright owner(s) are

credited and that the original publication in this

journal is cited, in accordance with accepted

academic practice. No use, distribution or

reproduction is permitted which does not

comply with these terms.

TYPE Perspective

PUBLISHED 09 October 2023

DOI 10.3389/fpubh.2023.1212583

Fu et al. 10.3389/fpubh.2023.1212583

Frontiers in Public Health 02 frontiersin.org

productivity gains and losses (2). e US has joined a small number

of countries (e.g., Italy) recommending both perspectives as reference

cases (3).

A pressing issue with such perspectives is that they may

insuciently highlight impacts on lived experience individuals,

including patients and families/caregivers (henceforth “patients” for

simplicity) (4). Although the societal perspective can capture some

patient-borne nancial impositions, they are aggregated with other

costs, raising the concern that a favorable societal-perspective prole

may not signal whether for patients an intervention is truly aordable,

adherable or otherwise impactful (5). e aordability concern is

accentuated when assessing innovative health interventions that

straddle the denition of prescription drugs and non-drug

technologies because the level of third-party coverage is a-priori

unclear; therefore, patients may face substantial increases in out-of-

pocket costs if an intervention is assigned to a category with lower

levels of coverage than its predecessors (5). ese interventions may

also impose negative impacts on patient lives that would remain

“hidden” within broader perspectives.

Herein, weargue that a potential solution—of particular interest

to public health professionals—is to supplement a societal- or payer-

perspective economic evaluation with an exclusive evaluation from

the perspective of patients. While guidelines for incorporating patient

inputs in HTA exist (6–8), a formal framework for conducting patient-

perspective economic evaluations has never been formulated to our

knowledge. As such, CEAs conducted with the patient perspective

oen vary in their coverage and denition of patient-borne costs (4).

In this Perspective paper, we aim to provide a comprehensive

discussion on the unique insights a patient-perspective economic

evaluation could yield to aid reimbursement decision-making

in healthcare.

2. Procedures

In this 2-part Perspective paper, we followed the Patient

Preferences in Benet–Risk Assessments during the Drug Life Cycle

project and a subsequent focus group discussion with HTA

representatives from Canada, Belgium and Germany (9, 10). In the

rst part of this paper, we formulated ve categories of health

interventions that could beused to ag when a supplementary analysis

might bewarranted through extensive discussion within our team.

e issues covered include household-level aordability; adherence;

unintended side eects; and burdens on daily living. A separate

category was created for gene therapy as it has been regarded as a

health technology particularly sensitive to the patient perspective (9,

10). Real-world examples are discussed.

To provide real-world perspectives on this topic, during December

2020, weinvited lived experience individuals from the Patient and

Family Advisors Network, a virtual network that comprises individuals

covered under Ontario’s publicly funded healthcare insurance system

who volunteer to serve as policy advisors for Ontario Health, to review

the dra of this paper. Using a convenience sampling methodology,

one researcher (DW) sent out email invitations where ve individuals

ultimately responded and agreed to review this paper. Wepresent the

comments from the 5 reviewers in Box 1. Weconclude this paper with

further discussions regarding when to conduct a patient-perspective

analysis alongside some cautionary notes. Currencies were adjusted to

2020 using the annual Consumer Price Index and then converted to

US dollars using purchasing power parities (11).

3. Types of health interventions that

may warrant a patient-perspective

analysis

3.1. Interventions that cross the deﬁnitional

boundary of drugs and non-drug

technologies or replace prescription drugs

e level of third-party coverage for drugs and non-drug

technologies varies, most likely due to diering societal preferences

for coverage and decision-making mechanisms. As one of the rst

countries to institutionalize HTA, Canada has operated a centralized

evaluative process for recommending funding for brand-name drugs

since 2003 through the Canadian Agency for Drugs and Technologies

in Health’s Common Drug Review. Funding recommendations

regarding non-drug technologies are made solely at the provincial

level with notable variability in processes and decisions (12). is

fragmentation creates issues for an emerging class of products that can

neither beclassied as a drug or non-drug technology. Patients who

seek access to these products face nancial obstacles as third-party

coverage may have varying criteria for coverage; one of our reviewers

shared this sentiment (Box 1). At the top of the scale, prescription

drugs are generally covered within a single program budget with

higher levels of coverage than within program budgets that cover

medical devices (13). us, webelieve funding decisions regarding

these novel products might benet from a separate patient-perspective

analysis as it may highlight the potentially large increase in out-of-

pocket costs. Wepresent the examples of EndeavorRx, a game-based

digital therapeutic devise approved in the US, and Abilify MyCite, a

prescription drug with a digital ingestion tracking system, under

this category.

e US Food and Drug Administration (FDA) has recently

approved interventions that either replace prescription drugs or

represent a hybrid of a drug and a medical device. An example of the

rst, EndeavorRx, was approved in 2020 as the rst game-based digital

therapeutic device prescribed for children with attention decit

hyperactivity disorder. is mobile device-based game involves

navigating through a course with obstacles that is designed to improve

attention function. EndeavorRx obtained FDA clearance through the

De Novo Classication Pathway due to the lack of a predicate device

on the market. To date, neither the FDA nor the manufacturer have

released information on pricing and insurance coverage; hence, it is

unknown what share of the cost families will face for this rst-of-its-

kind therapeutic device.

In 2017, Abilify MyCite was granted US market entry as the rst

prescription drug with a digital ingestion tracking system. Intended

to treat adults with schizophrenia, bipolar disorder and depression,

this combination product consists of Abilify (aripiprazole) tablets with

an ingestible sensor that sends signal to a wearable patch

communicating with a smartphone. Priced at 1,650 USD per month,

Abilify MyCite is 80-times more costly than its drug-only counterpart

and is covered in the US only for the most economically challenged

(Medicaid beneciaries). e cost-eectiveness of Abilify MyCite to

the payer/society has yet to be established, but with its high

Fu et al. 10.3389/fpubh.2023.1212583

Frontiers in Public Health 03 frontiersin.org

out-of-pocket costs, it is unlikely to beaordable to many households

without substantial third-party coverage.

3.2. Interventions that signiﬁcantly aect

patient adherence to protocol by having

unintended side eects

A health intervention that is likely to impact adherence and priced

substantially more than standard treatments warrants scrutiny within

the entire HTA process. A common method to account for

non-adherence in CEAs is through a small decrement in ecacy to

produce a de facto measure of eectiveness; however, the decrement

is commonly too small to result in any meaningful change in an

incremental cost-eectiveness ratio (ICER) that would impact HTA

recommendations (14). One of our reviewers, who are actively caring

for a child wearing a medical device, expressed frustration in

witnessing the side eects of the device and the lack of a more

adherable and comfortable alternative (Box 1). Meanwhile, adherence-

enhancing interventions usually demonstrate superior cost-

eectiveness—if not cost-saving—from the societal or payer

perspective (15). However, negative impacts on patient lives may

remain essentially hidden within broader perspectives as there may

besubstantial benets within these perspectives that could oset these

negative impacts to patients; therefore, patient-perspective evaluations

are needed to reveal potentially important patient-level eects; one of

our reviewers concurred (Box 1).

One example of such an intervention—FreeStyle Libre—is a

wearable ash glucose monitoring system for people with diabetes as

an alternative to nger-prick tests. e system comprises a disposable

subdural sensor and a device that receives and stores data. In 2020, the

Ontario Health Technology Advisory Committee (OHTAC) and the

HTA Advisory Board of Quebec have both recommended funding

FreeStyle Libre, despite analyses showing that it may not becost-

eective to payers compared to nger-prick tests (16). A

recommendation to fund the intervention was partially driven by

feedback from patients and caregivers who reported greater ease of

use permitting them greater control over their lives. is helped to

overcome uncertainty over its cost-eectiveness to improve blood

glucose stability.

While Abilify MyCite has already been mentioned, there is a

general class of drug-device hybrid products called digital pills

emerging that combine prescription drugs with an ingestible sensor,

a wearable patch and a mobile application (17). By continuously

tracking patients’ medication-taking behaviours, digital pills aim to

improve patient adherence, help forge self-care routines and enhance

patient-physician relationships. However, patients report fatigue and

disruption of daily routines by going through extensive training to

correctly operate the wearable patch and to successfully pair it with a

smartphone. is imposition on patient lives may begreater than the

burdens of manually remembering to take medications thereby

defeating the marginal benet associated with using digital pills (18).

Another issue is related to privacy, that is, who would beauthorized

to access patient data. At the extreme, these concerns may

bedisruptive leading to a refusal to take the medication. Furthermore,

there is the danger of device-associated emergent adverse events that

have implications for both patient well-being and adherence to

protocol (17). ese uncertainties raise questions regarding

willingness-to-pay out-of-pocket for a product carrying such risks for

improvements in adherence. A formal patient-perspective analysis

may beable to provide answers by soliciting inputs that highlight

these uncertainties.

Nirmatrelvir with ritonavir, sold under the brand name Paxlovid,

is another example of interventions that fall under this category. In

December 2021, the US FDA approved the use of Paxlovid for treating

mild-to-moderate COVID-19 under an emergency authorization.

Soon aer its approval, reports of side eects started to emerge, most

notably regarding the bitter metallic taste Paxlovid sometimes le in

mouth (“Paxlovid mouth”). Recent studies of “Paxlovid rebound,”

which refers to an asymptomatic or symptomatic resurgence of

COVID-19 aer nishing the full 5-day course of Paxlovid, suggest

this may bedue to patients skipping a dose to avoid the unwanted

aertaste of Paxlovid (19, 20). is conjecture requires more research

to conrm.

BOX 1 Comments received from lived experience individuals.

Interventions Comments

Interventions that cross the denitional boundary of drugs and non-drug

technologies or replace prescription drugs

“We too are oen bewildered on how to engage these new “cross-program”

interventions.”

Interventions that signicantly aect patient adherence to protocol by having

unintended side eects

“As a caregiver for a child with severe scoliosis, Iendured a daily struggle to try to

put him in a plastic back brace leaving me heartbroken as Ijust could no longer

force him to wear it. Iwas also consumed with guilt because without the brace the

alternative would bespinal surgery with all of the added risks involved.”

“Adherence is ultimately in the sphere of inuence controlled by the patient. It

therefore runs completely counter-intuitive for patients not to beengaged in

interventions that impact this critical nexus.”

Interventions that represent revolutionary treatments or even cures for genetic

disorders

“Is the revolutionary intervention truly a cure or does it just hide the genetic

disorder or just make it livable?”

Interventions previously approved for coverage but now targeted for potential

delisting or disinvestment

“is is an area that Iget most comments from other caregivers. ey do not

understand how their child, youth or adult can bedeprived of a treatment that was

working.”

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Frontiers in Public Health 04 frontiersin.org

3.3. Interventions that represent

revolutionary treatments or even cures for

genetic disorders

Recent breakthroughs have enabled new treatments for genetic

disorders that previously were considered untreatable. In clinical

trials, these treatments demonstrate high incremental eectiveness or

even a cure. While revolutionary, they may place added burdens on

patients’ lives or produce inadequately measured risks. Indeed, one of

our reviewers raised concern on the real-world outcome of these

treatments, and specically, if a cure was truly attainable (Box 1). In

this case, wesuggest that a separate patient-perspective analysis that

elicits inputs from patients and their families might provide important

insights to support informed decision-making. We talk about

treatments for spinal muscular atrophy as an example.

In 2017, Spinraza (nusinersen) was approved by the US FDA and

the European Medicines Agency for the treatment of spinal muscular

atrophy, a group of rare, genetic neuromuscular disorders that leads

to severe muscle weakness and progressive loss of motor function. In

2020, e Japanese Ministry of Health, Labour and Welfare approved

Zolgensma (Onasemnogene abeparvovec), a single-dose intravenous

gene replacement therapy that replaces Spinraza’s four loading doses.

Compared to Spinraza, Zolgensma is less costly (2 million USD vs.

2.2–10.6 million USD for Spinraza over a lifetime) and is potentially

superior to Spinraza by reducing treatment complexity (21). However,

patient representatives have voiced concerns on the durability of the

long-term benets of Zolgensma and on the uncertainty of treatment

pathways if gene expression diminishes over time (21). Furthermore,

to help better understand the particulars of treatment protocols,

patients may value genetic counseling, but the availability of such

counseling service is oen limited in real-world clinical settings—a

usually unmeasured shortcoming. None of these eects are captured

within current analyses.

3.4. Interventions with an expected ICER in

the southwest quadrant of the

cost-eectiveness plane from a payer or

societal perspective

Funding decisions are oen dicult for interventions that are less

costly but slightly less eective from payer/societal perspectives than

currently utilized therapies. Debates have been on the extent to which

the loss of a quality-adjusted life year (QALY) diers from the value

of acquiring a QALY. Review studies found Willingness-To-Accept/

Willingness-To-Pay ratios among health interventions to range from

1.9 to 6.4 (22). ese observations point to a kink in consumer

threshold values where patients are generally more reluctant to lose

than they are willing to gain. Currently, there is a lack of consensus on

how to address this potential asymmetry (23). Hence, weargue that

when confronted with this situation, a patient-perspective analysis in

which patient-level costs are weighted more heavily might help guide

funding decisions.

In 2002, the National Institute for Health and Care Excellence

(NICE) recommended vinorelbine as one option for second-line

treatment for advanced breast cancer (24). e only UK-based CEA

at that time concluded vinorelbine to beslightly inferior to taxanes in

terms of quality of life improvement, while being markedly cheaper.

e same study found the ICER of vinorelbine to be37,277 USD/

QALY (14,500 pounds/QALY in 1998 values) and 5,116 USD/QALY

(1,990 pounds/QALY in 1998 values)—in the southwest quadrant—

when compared to docetaxel and paclitaxel, respectively. Taking into

account the patient perspective, NICE recommended to keep funding

vinorelbine due to its safety and tolerability among patients

distinguishing vinorelbine as a more patient-friendly option

than taxanes.

An internet-mediated cognitive behavioral therapy for treating

mild to moderate depression is a more recent example (25). Trial

results suggest that this Swedish-recommended intervention produced

0.05 fewer QALYs over 12 months while saving 326 USD (2,664 SEK

in 2013 values) for the society compared to usual care (primary care

physician visits, nurse visits, antidepressants, face-to-face

psychotherapy and/or sick leave). e study concluded that this

therapy is at least as cost-eective as usual care and that the choice of

treatments ultimately relied on patient preferences regarding ease-

of-use, availability and willingness to wait for services.

3.5. Interventions previously approved for

coverage but now targeted for potential

delisting or disinvestment

ird-party payers sometimes must make decisions to delist a

previously reimbursed intervention. is may have profound and

sometimes unintended consequences to patients. According to one of

our reviewers, caregivers are usually baed by the delisting of a health

intervention that has been working for the patient (Box 1). It is

imperative that, prior to delisting, the perspective of patients’ needs to

beconsidered to avoid harm to subsets of patients. Furthermore, a

grace period during which patients can be phased out of these

interventions and transition into a new protocol should beclearly

dened and structured. Weargue that a patient-perspective analysis

may help clarify the relative costs and benets that will befall patients.

In 2017, the OHTAC recommended discontinuing public funding

for external cardiac loop recorders (ELR) for diagnosing cardiac

arrhythmia if the device relied solely on patient-initiated recordings.

In consideration of the recommendation, the Ontario Ministry of

Health now funds ELR only if it is operated by a cardiologist and

funding also continues for long-term continuous ambulatory

electrocardiogram monitors (ECGm), a more advanced alternative

(26). ese decisions were made on the basis that, despite a small

annual increase in provincial expenditures due to increased diusion

of ECGm, these expenses were justied given incremental

improvements in patient experiences. However, cardiologists voiced

concerns regarding the disinvestment decision as ELR and ECGm had

been traditionally used to diagnose dierent patient populations—one

that is able to self-monitor and the other monitored by a cardiologist,

respectively. Hence, a phasing out of reimbursement for ELR reduces

patient access to a proper diagnosis as a limited supply of cardiologists

must now supervise ELR testing (27). is issue cannot beoverlooked

because adoption and disinvestment policies need solid

implementation plans, including potential grace periods, to manage

unintended consequences in both cases.

ese unintended eects of disinvestment on patients and their

caregivers should bebetter anticipated. For example, expectorants and

mucolytics, that make coughing up mucus easier and less irritating,

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Frontiers in Public Health 05 frontiersin.org

were dropped in France from the publicly funded formulary in 2006

as a physician’s prescription was no longer needed. e resulting over-

the-counter market for these products saw price increases of up to

200%, the full cost of which was borne by patients leading to

aordability issues for those with lower incomes (28). A second

example involved the delisting of phlebotonics for chronic venous

diseases in Italy that was followed by an increase in hospitalizations

for venous insuciency (29). Perhaps, better consultations with

experts could assist implementation to either soen or prevent the

adverse eects noted.

4. Discussion

Existing health economic evaluation studies using the patient’s

perspective rarely provide a clear rationale on the conduct of a focused

patient-centred examination (4). As such, the preceding has been a

listing of situations in which patient-level assessment of both

aordability and level of imposition on patient lives is warranted

alongside a societal/payer perspective analysis to partially address

equity concerns. In terms of aordability, many jurisdictions provide

full coverage for those under the poverty line. For others, a limit is set

on out-of-pocket costs between 1% to 7.5% of income in order to

qualify for either tax deductions or credits, and/or government

programs that provide catastrophic coverage (30, 31). us,

aordability varies by level of income under the current patchwork

system (32). A marginal increase of at least 1% of income over

standard praxis might beworthy of notice for any subset of patients

based on the base threshold set for tax deductibility of medical

expenses in Germany, the lowest amongst western countries (31). No

similar threshold for imposition on patient lives neither exists nor is

recommended other than to suggest assessing the impacts individually

for each intervention.

ough perhaps not exhaustive, the list of situations provided

represent a rst attempt to elucidate a shortcoming in current

economic evaluation guidelines. We have shown that there is the

potential for substantial incongruencies in ndings between narrower

economic analyses from the perspective of patients than broader

analyses. ese dierences in ndings may suggest that net eects in

these broader perspectives tend to hide details that may beimportant

from the point-of-view of decision-making bodies. By weighing all

costs equally, these broader analyses may beunderestimating some

cost components that these bodies may wish to weigh more heavily

prior to concluding about whether and how to move forward.

Webelieve HTA agencies need to actively incorporate patient inputs

throughout the entire HTA process, but until we reach expert

consensus on how to quantitatively account for these data in cost-

eectiveness analyses, more feasible options include a qualitative

literature review about patient preferences and/or direct engagement

activities (such as a focus group discussion) with these individuals

(33). Caution must betaken, however, to not double-count time/

adherence costs that may already be captured within QALY

decrements and therefore should not beadded to nancial costs. At

this juncture, more work is needed to explicate the various situations

in which a patient-perspective economic evaluation is not only

warranted but potentially recommended.

Data availability statement

e original contributions presented in the study are included in

the article/supplementary material, further inquiries can bedirected

to the corresponding author.

Author contributions

RF, VN, ML, DW, EY, and EN: conceptualization, investigation,

and writing—review and editing. RF, VN, and EN: methodology. RF:

writing—original dra preparation. EN: supervision. All authors

contributed to the article and approved the submitted version.

Acknowledgments

Part of this paper was presented at the International Health

Economics Association (iHEA) 13th World Congress held virtually

during July 12–15, 2021. e opinions expressed in this publication

do not necessarily represent the opinions of Ontario Health (Quality)

nor the Ontario Ministry of Health. We would like to thank the

following lived experience individuals for their assistance and input:

Geo Feldman, Mark Freeman, Brian Huskins, Becky Quinlan, and

Maureen Smith.

Conﬂict of interest

VN was employed by Roche Diagnostics.

e remaining authors declare that the research was conducted in

the absence of any commercial or nancial relationships that could

beconstrued as a potential conict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors

and do not necessarily represent those of their aliated organizations,

or those of the publisher, the editors and the reviewers. Any product

that may be evaluated in this article, or claim that may be made by its

manufacturer, is not guaranteed or endorsed by the publisher.

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