Research
`
`JAMA Ophthalmology | Original Investigation
`Defining Nonadherence and Nonpersistence to Anti–Vascular Endothelial
`Growth Factor Therapies in Neovascular Age-Related Macular Degeneration
`
`Mali Okada, MMed; Tien Yin Wong, MD, PhD; Paul Mitchell, MD, PhD; Bora Eldem, MD; S. James Talks, MB Bchir;
`Tariq Aslam, PhD; Vincent Daien, MD, PhD; Francisco J. Rodriguez, MD; Richard Gale, MD; Jane Barratt, MSc, PhD;
`Robert P. Finger, MD, PhD; Anat Loewenstein, MD
`
`Supplemental content and
`Journal Club Slides
`
`IMPORTANCE Poor adherence or persistence to treatment can be a barrier to optimizing
`clinical practice (real-world) outcomes to intravitreal injection therapy in patients with
`neovascular age-related macular degeneration (nAMD). Currently, there is a lack of consensus
`on the definition and classification of adherence specific to this context.
`
`OBJECTIVE To describe the development and validation of terminology on patient
`nonadherence and nonpersistence to anti–vascular endothelial growth factor therapy.
`
`DESIGN, SETTING, AND PARTICIPANTS Following a systematic review of currently used
`terminology in the literature, a subcommittee panel of retinal experts developed a set of
`definitions and classification for validation. Definitions were restricted to use in patients with
`nAMD requiring intravitreal anti–vascular endothelial growth factor therapy. Validation by the
`full nAMD Barometer Leadership Coalition was established using a modified Delphi approach,
`with predetermined mean scores of 7.5 or more signifying consensus. Subsequent
`endorsement of the definitions was provided from a second set of retinal experts, with more
`than 50% members agreeing or strongly agreeing with all definitions.
`
`MAIN OUTCOMES AND MEASURES Development of consensus definitions for the terms
`adherence and persistence and a classification system for the factors associated with
`treatment nonadherence or nonpersistence in patients with nAMD.
`
`RESULTS Nonadherence was defined as missing 2 or more treatment or monitoring visits over
`a period of 12 months, with a visit considered missed if it exceeded more than 2 weeks from
`the recommended date. Nonpersistence was defined by nonattendance or an appointment
`not scheduled within the last 6 months. The additional terms planned discontinuation and
`transfer of care were also established. Reasons for treatment nonadherence and
`nonpersistence were classified into 6 dimensions: (1) patient associated, (2) condition
`associated, (3) therapy associated, (4) health system and health care team associated, (5)
`social/economic, and (6) other, with subcategories specific to treatment for nAMD.
`
`CONCLUSIONS AND RELEVANCE This classification system provides a framework for assessing
`treatment nonadherence and nonpersistence over time and across different health settings
`in the treatment of nAMD with current intravitreal anti–vascular endothelial growth factor
`treatments. This may have additional importance, given the potential association of the
`coronavirus pandemic on adherence to treatment in patients with nAMD.
`
`JAMA Ophthalmol. 2021;139(7):769-776. doi:10.1001/jamaophthalmol.2021.1660
`Published online June 3, 2021. Corrected on September 23, 2021.
`
`Author Affiliations: Author
`affiliations are listed at the end of this
`article.
`Corresponding Author: Mali Okada,
`MMed, Royal Victorian Eye and Ear
`Hospital, 32 Gisborne St E,
`Melbourne, VIC 3002, Australia
`(mali.okada@eyeandear.org.au).
`
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`

`Research Original Investigation
`
`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`S ince its introduction, intravitreal anti–vascular endo-
`
`thelial growth factor (anti-VEGF) injection therapy has
`transformed the treatment of neovascular age-related
`macular degeneration (nAMD).1 However, outcomes ob-
`servedinclinicalpractice(therealworld)generallydonotreach
`those seen in clinical trials,2 potentially because of lack of ad-
`herence or nonpersistence to the recommended trial regi-
`mens. Even within strict clinical trial settings, deviations from
`recommended protocols have often been associated with
`poorer visual health outcomes, with a recent secondary
`analysis3 of the Comparison of Age-Related Macular Degen-
`eration Treatment Trial (CATT) reporting worse visual acuity
`at 2 years in patients with missed or delayed visits.
`The World Health Organization defines adherence to long-
`term therapy as “the extent to which a person’s behaviour, cor-
`responds with agreed recommendations from a health care
`provider.”4(p3) In contrast, persistence is defined as “the du-
`ration of time from initiation to discontinuation of
`therapy.”5(p44) Previous discussions in ophthalmology have
`largely focused on how this behavior is associated with out-
`comes in glaucoma therapy. The concept of what constitutes
`adherence and persistence in nAMD, however, has not been
`clearly established. A recent systematic review6 of factors af-
`fecting treatment nonadherence and nonpersistence to anti-
`VEGF therapy in nAMD identified considerable variations in
`both terminology and descriptions of adherence and persis-
`tence,concludingthatuniformdefinitions,specifictothisfield,
`are required.
`The development of consensus definitions is important be-
`cause it enables consistent reporting and comparison of the
`true prevalence of nonadherence and nonpersistence. The ef-
`fectiveness of proposed interventions can also be analyzed. In
`this study, we describe the development and validation of defi-
`nitions for terms associated with adherence and persistence
`to anti-VEGF therapies in nAMD.
`
`Methods
`Subcommittee and Validation Group
`The nAMD Barometer Leadership Coalition is an interna-
`tional group of experts (with 14 members; M.O., T.Y.W., P.M.,
`B.E., S.J.T., T.A., V.D., F.J.R., R.G., J.B., R.P.F., and A.L. and 2
`nonauthors) in the field of nAMD, vision care, and healthy ag-
`ing. The nAMD Barometer program is a multiphase initiative
`established to develop robust evidence and provide recom-
`mendations on improving treatment in nAMD. As part of phase
`1 of this program, a subcommittee (with 8 members; T.A., J.B.,
`V.D., R.G., A.L., P.M., M.O., and T.Y.W.) was formed to lead the
`development and consensus validation of terms associated
`with adherence and persistence in nAMD.
`External endorsement of definitions was carried out by the
`wider members of the Vision Academy group. The Vision Acad-
`emy is an international collaboration of more than 80 expert
`physicians who provide guidance on management of various
`retinal diseases (a full list of members is at https://www.
`visionacademy.org/meet-our-members). Financial support for
`the nAMD Barometer program and the Vision Academy initia-
`
`Key Points
`Question What is the definition of adherence to and persistence
`with intravitreal therapy in neovascular age-related macular
`degeneration?
`
`Findings This expert consensus survey used a modified Delphi
`technique to establish a set of definitions for the terms adherence,
`nonadherence, persistence, nonpersistence, planned
`discontinuation, and transfer of care. A classification system based
`on the World Health Organization dimensions of adherence was
`developed for the reasons for nonadherence and nonpersistence.
`
`Meaning These definitions provide a framework when assessing
`patient engagement to intravitreal therapy, which may be useful in
`future studies identifying rates or risk factors for patient
`nonadherence or nonpersistence.
`
`tive is provided by Bayer Consumer Care AG, Basel, Switzer-
`land.
`
`Systematic Literature Review
`A systematic review with no date restrictions was conducted
`to identify original studies that included a definition of treat-
`ment adherence or persistence to anti-VEGF therapy for nAMD.
`Databases, including MEDLINE, Embase, and the Cochrane
`Central Register of Controlled Trials (CENTRAL), were searched
`on June 1, 2019. No eligibility restrictions were placed on the
`type of anti-VEGF or treatment regimen used. Studies were ex-
`cluded if interventions other than anti-VEGF injections or reti-
`nal conditions other than nAMD were evaluated. Terms such
`as compliance, nonattendance, discontinuation, dropout, ces-
`sation, and loss to follow-up were considered synonymous. Cur-
`rent definitions and usage of the terms nonadherence and non-
`persistence were extracted from the literature. The reasons for
`nonadherence and/or nonpersistence were derived from ar-
`ticles included in a recently published systematic review6 con-
`ducted by the same nAMD Barometer group.
`
`Definition Development, Validation, and Endorsement
`The term adherence, the preferred term in recent health lit-
`erature, was chosen for validation because it reflects a more
`proactive health care interaction compared with the more pas-
`sive term compliance.4 The negative connotations of blame as-
`sociated with compliance have also led to its decreasing use.
`Similarly, the term persistence was chosen instead of discon-
`tinuation to mirror this shared health-engaging behavior.
`A modified Delphi approach was used to establish con-
`sensus definitions (Figure; further details are provided in the
`eAppendix in the Supplement). Using the results of the sys-
`tematic review as a starting point, proposed definitions for ad-
`herence and persistence were drafted. These initial defini-
`tions were discussed and refined among subcommittee
`members via virtual meetings and email correspondence to de-
`termine the most appropriate definitions to put forward for
`validation.
`TheDelphimethod,astructuredtoolforestablishinggroup
`consensus, was then used to validate the initial set of
`definitions.7 This approach involved providing experts with
`
`770
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`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`Original Investigation Research
`
`classifications finalized
`
`Definitions and
`
`to planned discontinuation
`discontinuation, amended
`New definition, planned
`
`from Vision Academy
`following feedback
`or transfer of care,
`
`nAMDindicatesneovascularage-relatedmaculardegeneration;WHO,WorldHealthOrganization.
`
`Academy endorsement;
`
`detect bias in Vision
`Tests conducted to
`
`no bias found
`
`amendments suggested
`definition, with minor
`endorsement of new
`
`Vision Academy
`
`new definition sent to
`Endorsement survey for
`
`Vision Academy
`
`definition and updated
`
`Validation of new
`
`Leadership Coalition
`
`nAMD Barometer
` classifications by
`
`classifications with full
`definition and updated
`Delphi survey on new
`
`Leadership Coalition
`
`nAMD Barometer
`
`Academy endorsement;
`
`detect bias in Vision
`Tests conducted to
`
`no bias found
`
`Vision Academy
`definitions by
`Endorsement of
`
`Endorsement survey for
`
`Vision Academy
`definitions sent to
`
`and classifications by
`Validation of definitions
`
`Leadership Coalition
`
`nAMD Barometer
`
`Leadership Coalition
`full nAMD Barometer
`classifications with
`
`definitions and
`Delphi survey on
`
`adherence categories), following further discussion
`and update of classifications (in alignment with WHO
`Addition of new definition, planned discontinuation,
`
`among nAMD Barometer subcommittee
`
`classifications
`definitions and
`
`Update of
`
`via email correspondence
`Barometer subcommittee
`
`Feedback from nAMD
`
`Barometer subcommittee
`
`via 2 virtual meetings
`
`Feedback from nAMD
`
`development of definitions
`
`Literature search and
`
`and classifications
`
`Development
`
`Refinement
`
`Validation
`
`Endorsement
`
`Finalization
`
`Stage 2
`
`Stage 1
`
`Figure.ModifiedDelphiConsensusProcessandDevelopmentofValidatedDefinitions
`
`jamaophthalmology.com
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`

`Research Original Investigation
`
`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`a circulating series of questionnaires. After each round, the
`questionnaire was modified according to anonymized group
`feedback before it was re-sent, with the goal of working
`toward mutual agreement in the subsequent round. Specifi-
`cally, for this study, a draft of the definitions and factors
`affecting treatment adherence or persistence developed by
`the subcommittee was circulated to the full Leadership
`Coalition for consensus validation. Each member of the
`Leadership Coalition was asked to assign a score from 1 to 10
`to indicate their level of agreement with the proposed defi-
`nitions, where 1 indicated strongly disagreeing and 10
`strongly agreeing. If respondents disagreed, they were
`required to provide anonymized feedback on reasons for
`disagreement and suggested changes to the proposed defi-
`nition. The mean score from all respondents was calculated,
`and a predetermined cutoff value of 7.5 or more was estab-
`lished for consensus. If the mean score was 7.5 or more,
`consensus was reached and the term validated. If the mean
`score was less than 7.5, then consensus was not reached,
`and the definition was amended according to the feedback
`and sent back for a further round of evaluation. This process
`was repeated until consensus was reached on all terms. The
`modified Delphi consensus and validation process was com-
`pleted over a period from November 2019 to May 2020.
`The validated set of definitions was then sent to the wider
`Vision Academy group members for endorsement via an on-
`line survey. Respondents were asked to rate their agreement
`with the proposed definitions with the options strongly agree,
`agree, neither agree nor disagree, disagree, and strongly dis-
`agree. A target of more than 50% of members responding was
`required for the survey to be valid. Participants were also asked
`for their country of practice as well as the reimbursement sta-
`tus of treatment (ie, mostly reimbursed or mostly out of pocket)
`to ascertain if this may have influenced the response. Biases
`were assessed using χ2. Endorsement was established if 50%
`of respondents or more either agreed or strongly agreed. Means
`and SDs were calculated using Excel version 16.48 (Mi-
`crosoft).
`
`Results
`Current Definitions in the Literature
`The systematic review identified 21 studies8-28 that reported
`definitions of compliance, adherence, persistence, discontinu-
`ation, and/or loss to follow-up. Additional insights into rea-
`sons for nonadherence and nonpersistence were also in-
`cluded from 9 studies.29-37 Definitions were extracted from the
`existing literature (Table 1).
`
`Proposed Definitions for Adherence and Persistence
`The new validated definitions are described in Table 2. A single
`definition for each term was developed to ensure consis-
`tency and simplicity of use in everyday practice. To facilitate
`this, the validated definitions used attendance at any sched-
`uled clinic visit (both monitoring and injection visits) as a mea-
`sure of adherence or persistence. This enabled the terminol-
`ogy to be used across different injection regimens (ie, both as
`
`Table 1. Current Definitions Extracted From the Systematic Review
`
`Term
`Nonadherence
`Synonyms:
`noncompliance,
`absenteeism, and
`nonattendance
`
`Nonpersistence
`Synonyms:
`discontinuation, dropout,
`cessation, and loss to
`follow-up
`
`Definitions in the existing literature8-30
`• No treatment or monitoring visit at least
`once every 6 or 8 wk
`• Extreme violation of prescribed treatment
`regimen
`• Nonattendance at every clinic appointment
`• <8 Injections over 12 mo
`• Visits outside of the prescribed window of
`28 ± 7 d
`• Treatment discontinuation before initial 12
`mo, study period end, or permanently
`• No treatment or monitoring visit for 4, 6, 12,
`or 24 mo
`• No follow-up by an ophthalmologist for 3 mo
`• No follow-up within a 12-mo period after
`receiving at least 1 anti–vascular endothelial
`growth factor injection
`
`needed and treat and extend), as well as different practice set-
`tings.
`
`Adherence and Nonadherence
`The term adherence was broken down into 2 categories: fully
`adherent and adherent (Table 2). The term fully adherent re-
`fers to ideal practice, with complete observance of all sched-
`uled visits. However, in clinical practice, this is often unreal-
`istic, and most patients would be classified as nonadherent
`using this all-or-nothing approach. Therefore, a less strin-
`gent assessment of adherence was also established to pro-
`vide a stepdown level of gauging adherence, which, although
`imperfect, was more achievable in clinical practice. A defini-
`tion of no more than 1 missed appointment over a 12-month
`period was chosen because this reflects the commonly used
`definition of more than an 80% cutoff for classification of what
`constitutes good adherence to general medications.38,39 When
`a patient is nonadherent and misses appointments, the num-
`ber of missed visits is determined by the total potential visits
`during the nonadherent period using the last known visit in-
`terval. For example, if a patient is recommended to have in-
`jections every 4 weeks but does not return for 4 months, then
`the number of missed visits is 3 if the patient attends all fol-
`low-up visits for the remaining 12-month period. If there is a
`further period of missed appointments within this 12-month
`period, the results are cumulative. Adherence is determined
`every 12 months, so changes in adherence patterns over time
`can be assessed per year (eg, for a patient with 3 years of treat-
`ment, adherence is given per year [ie, for years 1, 2, and 3]).
`The timing of the visit was also considered important for
`calculating adherence, with a margin of 2 weeks’ delay al-
`lowed, after which the physician-recommended visit is con-
`sidered missed. The 2-week cutoff was based on logistics of
`scheduling appointments in clinical practice. Visits outside of
`this recommended time frame were also recorded as missed,
`regardless of whether an appointment was actually booked.
`This accounted for variations in health care models, with some
`systems requiring patients to call up and initiate the next ap-
`pointment vs others in which the clinic automatically makes
`the bookings. Delays attributable to systemic factors, such as
`lack of clinic capacity, as a reason for nonadherence were also
`captured in this way.
`
`772
`
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`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`Original Investigation Research
`
`Table 2. Validated Definitions for Adherence and Persistence
`to Anti–Vascular Endothelial Growth Factor Therapy
`in Neovascular Age-Related Macular Degeneration
`
`Definition
`Adherence
`Full adherence
`Attendance at every scheduled clinic visit
`(treatment or monitoring) and undergoing
`every treatment or monitoring procedure
`advised by the treating physician over 12 mo
`Adherence
`Missing ≤1 treatment or monitoring
`visit scheduled as advised by
`the treating physician over 12 moa,b
`Nonadherence
`Missing ≥2 treatment or monitoring
`visits scheduled as advised by
`the treating physician over 12 mob
`Persistence
`Persistence
`Maintaining treatment or monitoring
`as advised by the treating physician and
`attending the most recent appointment
`within the last 6 moc
`Nonpersistence
`Not attending any treatment or monitoring
`visit for any reason within the last 6 mo or
`not scheduling follow-up appointments
`for any reason for 6 mod
`Planned discontinuation and transfer of care
`Planned discontinuation
`Lack of treatment response (treatment
`futility) or no disease activity requiring
`ongoing treatment, as judged by
`the treating physician
`Transfer of care
`The ongoing management of the patient’s
`neovascular age-related macular
`degeneration, transferred
`to another physician
`
`Mean (SD) Delphi score
`Stage 1
`Stage 2
`
`9.69
`(0.61)
`
`9.91
`(0.31)
`
`8.75
`(2.20)
`
`9.82
`(0.40)
`
`8.33
`(2.17)
`
`9.67
`(0.67)
`
`9.31
`(0.82)
`
`9.82
`(0.40)
`
`9.50
`(0.67)
`
`9.27
`(1.27)
`
`NA
`
`9.27
`(1.27)
`
`Abbreviation: NA, not applicable.
`a A visit is considered missed if the recommended appointment date is
`exceeded by more than 2 weeks for any reason. The number of missed visits is
`determined based on the total potential visits missed during the nonadherent
`period, using the last recommended visit interval.
`b The period of 12 months begins from the time of the first injection. For
`subsequent years of treatment, adherence is calculated every 12 months.
`c A patient is not required to be adherent to be persistent.
`d The first day of the 6-month period after the most recent appointment
`attended should serve as the date of onset of nonpersistence. A minimum of 6
`months since the first injection is required to assess persistence.
`
`For patients with bilateral nAMD, adherence was also cal-
`culated per patient rather than per eye, using the eye with the
`shortest visit interval for determination. For example, a pa-
`tient receiving injections once every 12 weeks in 1 eye and once
`every 4 weeks in the fellow eye who does not attend any vis-
`its for 12 weeks is considered nonadherent. This allows for fac-
`tors such as bilaterality in disease or nonsimultaneous injec-
`tions to be easily identified as barriers to treatment.
`
`Persistence and Nonpersistence
`The term nonpersistence was defined as nonattendance of any
`treatment or monitoring visit within the last 6 months. In de-
`
`jamaophthalmology.com
`
`termining the 6-month nonattendance cutoff, the subcom-
`mittee agreed that a 4-month period was too short, because
`some treat-and-extend regimens allow extension up to 4
`months (16 weeks). In contrast, 12 months was considered too
`long, because there are very few circumstances in which pa-
`tients would not have either a monitoring visit or injection for
`a full year and still be considered to be engaging in therapy for
`nAMD.
`Accordingly, a minimum assessment period of 6 months
`since the first injection is required to gauge levels of persis-
`tence, because this is the least amount of elapsed time that
`meets the definition of nonpersistence. For example, a pa-
`tient who received an injection and was scheduled to return
`in 4 weeks but did not return for either monitoring or further
`injections for 7 months would be considered nonpersistent.
`However, if at the time of assessment, only 4 months had
`passed since their last visit, although the patient would be con-
`sidered nonadherent (having missed 3 potential visits), per-
`sistence cannot be determined. The tolerance threshold of
`missed appointments for patients who are adherent was still
`stricter than that allowed in the definition for persistence. In
`this way, a patient could be classified as persistent while not
`necessarily being adherent, but not vice versa.
`
`Planned Discontinuation or Transfer of Care
`An additional 2 terms, planned discontinuation and transfer of
`care, were also developed to account for those patients for
`whom treatment cessation is intentional and not because of
`nonpersistence. Patients are recorded as persistent if they at-
`tend visits with other physicians or clinics, as long as it was
`for the purpose of monitoring or treating their nAMD and it was
`possible to obtain ongoing treatment details. If a patient is
`known to have followed up with another physician but treat-
`ment details are not known, then the patient journey would
`be designated as a transfer of care.
`
`Proposed Classification of Factors Affecting Nonadherence
`and Nonpersistence
`The reasons for treatment nonadherence and nonpersistence
`were classified according to the World Health Organization di-
`mensions of adherence4: (1) patient associated, (2) condition
`associated, (3) therapy associated, (4) health system and health
`care team associated, and (5) social/economic, and (6) other.
`Within these dimensions, subcategories specific to intravit-
`real therapy to nAMD were created (Table 3). The subcatego-
`ries were determined based on common factors identified from
`the previously published systematic review.6 There was no
`limit on number of factors per patient, since reasons may be
`multifaceted or interconnected.
`
`Discussion
`There is currently no universal agreement of what adherence
`and persistence to intravitreal injection therapy is in nAMD.
`In this study, we have provided a set of definitions that assess
`the extent and cause of treatment nonadherence or nonper-
`sistence specific to this context.
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`Research Original Investigation
`
`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`Table 3. Validated Classification of Reasons for Treatment Nonadherence
`or Nonpersistence to Therapy in Neovascular Age-Related
`Macular Degeneration
`
`ries specific to patients receiving intravitreal injections. This
`helps to align this system with other discussions of adher-
`ence in the health literature yet keeps it relevant to the
`management of nAMD. However, it is worth noting that
`although factors have been classified into distinct dimen-
`sions, causes can be bidirectional or interdependent. For
`example, a patient’s perceived treatment burden may be
`associated with system issues, such as the distance to spe-
`cialist treatment, which is also associated with social barri-
`ers, such as access to transportation. Therefore, for an indi-
`vidual patient, there can be multiple attributable reasons.
`
`Limitations
`There are several potential limitations to the proposed classi-
`fication system. First, these definitions were established from
`consensus opinions and have yet to be tested on patient data
`sets. This is similar to the development of other classification
`systems currently in use, such as the definitions of atrophy as-
`sociated with AMD, which was established using expert con-
`sensus at the Classification of Atrophy Meeting. However, the
`clinical relevance of our proposed system will be examined in
`the next phase of the nAMD Barometer initiative, in which
`these definitions will be used in observational studies of pa-
`tients, clinicians, and caregivers and their perceptions of bar-
`riers to treatment.
`A further limitation to this classification system is that
`these were established in the setting of an industry-
`sponsored group, which could introduce subconscious bias to
`the recommendations. The use of objective evidence, such as
`the systematic literature review and the World Health Orga-
`nization dimensions of adherence, as the starting basis for de-
`veloping the definitions is intended to minimize any poten-
`tial bias.
`An additional consideration is that the maximum num-
`ber of missed visits allowed to still be considered as adherent
`was 1 per 12-month period, which may not truly reflect all cur-
`rently used treatment regimens. The rationale for only 1 visit
`was based on a treat-and-extend regimen in the first year. The
`absolute minimum number of injections in the first 12 months,
`assuming a loading dose of 3 injections followed by a 2-weekly
`extension at every visit, would be approximately 6 injec-
`tions, and the 80% calculation refers to this scenario. How-
`ever, although the treat-and-extend approach is increasingly
`preferred, not every physician or health system uses this regi-
`men. Furthermore, the minimum number of injections per 12-
`month period will depend on the patient’s disease activity and
`point in their treatment trajectory. For example, a patient may
`be on a 16-weekly interval in their third year of treatment, for
`which an adherence rate of 80% would be 2.4 visits of 3 ex-
`pected visits per year. Nevertheless, to provide ease of use and
`better reflect the critical aspect of the first year of treatment,
`we felt that using a constant and whole number (ie, missing
`no more than 1 visit per 12 months), rather than percentage of
`visits, was a reasonable compromise. Finally, usage of this pro-
`posed classification system may be limited when used in stud-
`ies where the intended treatment schedule is not recorded. For
`example, in some electronic or insurance databases, only the
`actual date of visit may be recorded. Therefore, missed visits
`
`Regeneron Exhibit 1183.006
`jamaophthalmology.com
`Regeneron v. Novartis
`IPR2021-00816
`
`Classification
`Patient
`associated
`
`Condition
`associated
`
`Therapy
`associated
`
`Subcategories
`• Patient education level or understanding of
`the need for treatment
`• Patient loss of motivation
`• Ocular comorbidities
`• Nonocular comorbidities or general health
`problems
`• Consent withdrawal
`• Treatment burden
`• Other
`• Treatment success (patient determined)
`• Treatment failure (patient determined)
`• Treatment contraindication
`• Poor baseline visual acuity
`• Other
`• Treatment discomfort
`• Adverse event
`• Fear of injections
`• Other
`• Administrative problem
`• Access to treatment (eg, appointment
`availability)
`• Distance to treatment
`• Other
`Social/economic • Lack of transportation
`• Caregiver availability (eg, to attend clinic
`appointment with patient)
`• Direct cost or reimbursement issue
`• Indirect costs (eg, parking fees,
`productivity loss)
`• Other
`• Death
`• Uncontrollable/unpredictable event (eg,
`restrictions or deferral of appointment
`because of COVID-19 pandemic)
`
`Health system
`and health care
`team associated
`
`Other
`
`Mean (SD)
`Delphi score
`9.27 (1.56)
`
`9.27 (1.42)
`
`8.64 (2.34)
`
`8.73 (2.33)
`
`8.82 (2.34)
`
`9.64 (0.67)
`
`The definitions proposed here are designed to be suffi-
`ciently flexible to cover all currently used injection regi-
`mens for nAMD. Although there has been a transition to
`favoring the treat-and-extend protocol in recent years,
`using timing of scheduled visits rather than the number of
`injections enables these definitions to be used by practition-
`ers across different health systems. However, it was decided
`to restrict these definitions and classification to therapy for
`nAMD with anti-VEGF only, because intravitreal injection is
`usually more time critical in this condition compared with
`other indications, such as diabetic macular edema. The rea-
`sons behind nonadherence or nonpersistence are also more
`likely to differ in this population of older patients, com-
`pared with those with macular edema from other retinal
`diseases.40
`This new classification system also addresses some of
`the shortcomings in previous definitions, one of which was
`the grouping of patient death or planned discontinuation
`because of treatment futility with other reasons for
`nonpersistence.6 Clearly, these represent different scenarios
`than patients who are nonpersistent because of factors such
`as lack of transportation, for example. In addition, the distinc-
`tion between the terminology of adherence and persistence
`is also clarified here, because patients can be nonadherent yet
`still persistent.
`The classification system for reasons for nonadherence
`or nonpersistence was also modeled on the World Health
`Organization dimensions of adherence but had subcatego-
`
`774
`
`JAMA Ophthalmology July 2021 Volume 139, Number 7 (Reprinted)
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`Downloaded From: https://jamanetwork.com/ on 04/04/2022
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`

`

`Defining Nonadherence and Nonpersistence to Anti–VEGF Therapies in Neovascular Age-Related Macular Degeneration
`
`Original Investigation Research
`
`or visits outside the 2-week margin may not necessarily be de-
`tected.
`
`Conclusions
`Understanding the prevalence and reasons behind nonadher-
`ence and nonpersistence is important, in that they remain sig-
`nificant barriers to optimizing outcomes for patients with
`nAMD. The validated definitions and classification system pro-
`posed in this article provide an opportunity to raise aware-
`ness among health care professionals and patients. It also sets
`outauniformlanguageforuseinfutureresearchforeasiercom-
`parison. The current COVID-19 pandemic in particular has pre-
`sented unprecedented challenges for patient management. It
`is likely that a considerable proportion of patients with nAMD
`will have had their treatment interrupted during this crisis.41
`Consistent terminology will be important as we begin to as-
`sess the effect of the pandemic on patient outcomes.
`
`Consensus definitions also establish benchmarks to
`measure the effectiveness of interventions designed to
`improve adherence and persistence to anti-VEGF injections.
`As part of the nAMD Barometer project, initiatives currently
`underway include quantifying nonadherence and nonpersis-
`tence using this proposed framework in 2 separate studies.
`The f