Considering Patient Preferences When Selecting Anti–Tumor Necrosis Factor Therapeutic Options

The use of anti–tumor necrosis factor (TNF) medications for the treatment of chronic inflammatory conditions, such as rheumatoid arthritis (RA), Crohn’s disease, or psoriasis, represents a large and growing healthcare expenditure. For example, a 2013 sales forecast for adalimumab, the most frequently used injectable anti-TNF, projected continued growth in annual sales from $9.2 billion to $11.2 billion in 2016,¹ and infliximab, an intravenous (IV) infusion anti-TNF, generated more than $7 billion in revenue in 2012.²

Parallel with the increased use of the anti-TNFs, there has been emerging evidence that the anti-TNFs have similar effectiveness and safety profiles,^3-6 giving patients more options in terms of medication route and frequency of administration. Infliximab, the first anti-TNF approved by the US Food and Drug Administration (FDA),⁷ is available only as an IV infusion and requires administration by a medical provider every 4 to 8 weeks.8 Patients receiving infliximab have several options regarding where the infusion is administered, all of which include administration by a healthcare professional, including at a medical facility, such as a physician’s office; an infusion center; an outpatient department of a hospital; or at home by a home health agency nurse, all of which are typically covered by insurance plans.

Subcutaneous (SC) anti-TNFs, including etanercept, adalimumab, certolizumab pegol, and golimumab, offer the convenience of self-injection, but they need to be administered on a more frequent schedule, from twice weekly to once monthly, depending on the agent and its FDA indication.^9-12 Since the 2013 FDA approval of its IV formulation, golimumab is the only anti-TNF agent available as both SC and IV medications.¹¹

In the current healthcare environment of offering a wide variety of treatment options with similar clinical effectiveness but differing routes of administration and dosing regimens, there is an opportunity for patient preferences to play a greater role in the selection of agents. IV treatment may appeal more to patients who desire greater physician control over medication administration, who feel the need for a physician’s presence for a sense of safety, or who have difficulty complying with a self-injecting regimen.¹³

By contrast, despite a more frequent dosing regimen, SC administration offers patients more flexibility and convenience, because their medication can be administered during the time selected by the patient, with no need for medical appointments. Self-administration also eliminates the need to travel to the physician’s office or to other facilities, which usually needs to occur during business hours, thus making it an attractive option for individuals who are more active or who are in the workforce.¹³

Previous research on mode of administration preferences among anti-TNF users is scarce; especially lacking are US-based studies and studies examining a wide variety of indications. A small British study of preferences among 109 patients with RA showed that 48% of patients preferred to administer their medication themselves, whereas 41% preferred having the hospital staff administer the treatment.¹³

A different single-center British study of 100 patients with RA reported that patients receiving anti-TNF therapy and those not yet receiving biologic therapies preferred SC injection as their first choice over intramuscular or IV administration; they also preferred administration at home rather than in an outpatient or inpatient setting.¹⁴

A 2009 Italian study of 802 patients with RA showed that both IV and SC anti-TNFs were well accepted, with patients evenly split in terms of their preferences for the route of administration.¹⁵ Finally, a recent study of 107 patients with RA in Denmark reported that IV administration was preferred by 85% of patients who are currently receiving IV therapies, and SC routes were preferred by 71% of patients who are currently receiving SC therapies.16 We identified only a single US-based study on the topic: a 2008 analysis of 50 patients with irritable bowel disorder reported a slightly greater percentage (54.3%) of patients expressing preference for the SC route of delivery, and all patients who had experienced both routes also preferring SC administration.¹⁷

Our study was designed to evaluate a large, geographically and clinically diverse, sample of US patients in 2012 who were using anti-TNFs regarding their preferences for route and place of administration, treatment satisfaction, and information sources related to their choice of therapy. This information is especially timely, because there are currently many more anti-TNFs available than before.

Methods
Study Design
This prospective observational study assessed the outcomes of 2 groups of patients: those receiving an IV infusion anti-TNF (ie, infliximab) and those receiving an SC anti-TNF (ie, adalimumab, golimumab, etanercept, or certolizumab pegol).

The study consisted of a cross-sectional patient survey, with all survey-related materials approved by a central Institutional Review Board before the start of the survey. Eligible patients were included if they were fluent in English, could communicate by telephone, and consented to the study. Patients were contacted by telephone between November 29, 2012, and December 19, 2012, and either completed a 30-minute survey by telephone with the interviewer or via the Internet. Patient-level data were handled in compliance with the Health Insurance Portability and Accountability Act of 1996.

The survey questionnaire was developed specifically for the study and included questions about patients’ demographic and socioeconomic characteristics, use of anti-TNF agents, site of administration, preferences for IV or SC therapy, interest in anti-TNF home therapy, and their information sources about anti-TNFs. A sample questionnaire with selected questions from the survey is listed in the Appendix. A validated patient-reported outcome instrument, the Treatment Satisfaction Questionnaire for Medication (TSQM) version II, was used to assess treatment satisfaction.

Patient Eligibility
The HealthCore Integrated Research Database was used as a sampling frame to identify the eligible patient population, consisting of patients who were using an anti-TNF medication and who had been diagnosed with 1 or more of the FDA-approved indications for anti-TNF agents. Specific patient inclusion criteria included (1) at least 1 claim for infliximab, adalimumab, golimumab, etanercept, or certolizumab pegol between March 2012 and August 2012, and at least 1 medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of Crohn’s disease, RA, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis during the 6-month period before the initiation of the anti-TNF agent; (2) age ≥18 years; (3) health plan membership at the time of patient sample list creation; (4) nonmissing telephone number and/or address; and (5) not being on the HealthCore do not call list.

The survey population was further restricted to a maximum of 6000 patients, selected at random, with an overrepresentation of patients taking infliximab and patients with a diagnosis of Crohn’s disease (regardless of whether they used infliximab or an SC medication). Patients who received infliximab were oversampled to facilitate comparisons between the main groups of interest (IV and SC), and patients with Crohn’s disease were oversampled to facilitate subgroup analysis by condition.

Outcomes
Patient preferences and treatment satisfaction. Patients were asked to rank their preference for the route of administration of anti-TNFs, with options of expressing strong preference for an injectable, slight preference for an injectable, slight preference for an infusion, or strong preference for an infusion. All patients were asked this question, regardless of whether they had an experience with single or multiple routes of administration. We used a forced-choice method to elicit definitive opinion, because we were interested in providing the most actionable data for decision makers. For similar reasons, patients were asked to choose whether they would like to take their anti-TNF medications at home using a Likert scale with an even number of responses.¹⁸

For the assessment of anti-TNF treatment satisfaction, we used an 11-item validated satisfaction questionnaire, the TSQM version II, which allows for comparisons across various medication types and therapeutic areas. Four subscale scores were obtained, including effectiveness, side effects, convenience, and global satisfaction with treatment.¹⁹ The subscale scores each ranged from 0 to 100, with higher scores representing greater satisfaction with the effectiveness, lack of side effects, convenience, and global satisfaction of the respondents with their anti-TNF medications.

Information sources related to choice of therapy. Patients were also asked whether their doctor had discussed prescribing for them any anti-TNF medication other than what they were currently taking. The patients who reported having such discussions were further asked whether the physician expressed preferences for one drug over another, and if so, whether the physician explained the reasons for that preference.

In addition, patients were asked to report where they usually received information about anti-TNF therapies, to report the mode by which they were most interested in receiving information, and to rank their interest in receiving additional information, on a scale from 1 to 5, where 1 was completely not interested and 5 was extremely interested.

Statistical Methods
Sample size. The final list of patients eligible for the survey consisted of 6000 patients. All available patients with a claim for infliximab (N = 2095), as well as all patients with a diagnosis of Crohn’s disease (N = 1914) were retained in the study sample; the remaining patients who met the initial inclusion criteria (N = 2948) were randomly selected from the larger patient population of patients receiving anti-TNFs. The targeted number of completed surveys was set at 500, with the survey phase ending after reaching the targeted number.

Data analysis. This was a descriptive study. For each of the 2 anti-TNF groups (ie, IV and SC), summary statistics, including mean and standard deviation, were provided for continuous variables; counts and percentages were provided for categorical variables. The differences between the 2 groups were compared using a t-test for continuous variables and a χ² test for categorical variables. Statistical analyses were conducted with SAS version 9.1 software (SAS Institute; Cary, NC). All statistical tests were 2-sided and were performed at a 5% level of significance.

Results
Of the 6000 patients included in the final patient list, 1370 patients had been contacted at the point when the target numbers of 500 complete surveys and 7 partial surveys were reached, resulting in a cooperation rate (ie, the percentage of respondents agreeing to be interviewed of the eligible patients contacted) of 37%.

Among respondents with completed surveys, the IV group consisted of 202 patients (40%) and the SC group consisted of 298 patients (60%).

Patient Characteristics
Patients’ characteristics are listed in Table 1. The patient age distribution was different between the groups; IV users were more likely to be in the younger age-group (30.7% in the IV group vs 21.5% in the SC group) and in the older age-group (16.3% in the IV group vs 5.4% in the SC group), whereas SC patients were more likely to be of working age (73.2% in the SC group vs 53% in the IV group; P <.001).

As expected, because autoimmune diseases are more common in women, the respondents were more likely to be women (69.3% in the IV group and 67.1% in the SC group; P = .606). Respondents had similar distributions of household income. An overwhelming majority of respondents were white—more than 90% of patients in each group. In addition, similar proportions of both groups had a college or university degree (43.1% in the IV group, 46.3% in the SC group; P = .736).

A higher percentage of respondents in the SC group were employed full time outside the home than in the IV group (59.4% in the SC group vs 48% in the IV group; P = .039). The IV group was more likely to be composed of patients with Crohn’s disease (38.6% vs 25.8% in SC group; P = .004) and was less likely to include patients with RA (45.5% vs 50.7% in the SC group; P = .007) and those with plaque psoriasis (5.9% vs 16.8% in the SC group; P = .001).

The majority of patients reported using anti-TNFs for at least 1 year, but the IV group had a higher percentage of patients in the longest treatment category (84.2% in the IV group vs 74.8% in SC group; P = .011; Table 1). In addition, 48 (23.8%) patients in the IV group had previously used an SC anti-TNF and 61 (20.5%) patients in the SC group had previously used an IV anti-TNF.

Outcome Measures
Patient preferences and treatment satisfaction. Noticeably, there was high correspondence between the expressed preference and the administration route for the medications that patients were currently taking (Table 2). This pattern was present regardless of the indication, and it held for patients who had previously used a different administration route (results are available on request). However, patients in the SC group reported a higher preference for the route of administration they were currently using compared with the IV group: 89.9% of patients in the SC group reported either a slight or strong preference for an SC anti-TNF, whereas only 71.8% of patients in the IV group had a slight or strong preference for infusions (P <.001).

We observed differences in preference regarding the location where patients received their treatment (facility-based vs home services). When asked whether they would like to be able to take anti-TNF medication at home, 46.1% of patients in the IV group reported either somewhat agreeing or strongly agreeing, indicating significant interest in being able to receive the medication outside of medical facilities (Table 3). In the SC group, a very high proportion (96.3%) of patients expressed preference for receiving medications at home. Although 46.1% of patients receiving IV medications liked the home administration option, only 1.5% were using it (results are available on request).

The results from the validation instrument TSQM version II indicated treatment satisfaction to be high and similar between the groups (Table 4). In terms of specific subscale scores, patients in the IV group reported higher effectiveness scores than in the SC group (82.4 ± 16 and 78.8 ± 19.3, respectively; P = .025) but lower convenience scores (75.6 ± 15.6 compared with 79 ± 14.8, respectively; P = .015). There were no significant differences between the 2 groups on the side effects subscale scores or on the global satisfaction subscale scores.

Information sources related to choice of therapy. Slightly less than half of the respondents reported that they had had a discussion with their physician about alternative anti-TNF medications (45.5% of the IV group and 49.7% of the SC group; P = .366; Table 5). Those rates fluctuated depending on the condition, but differences between groups did not reach statistical significance in either of the condition-specific subgroups (results are available on request).

Among the patients who had a discussion with their physician about an alternative anti-TNF, approximately 66% of patients (63% in the IV group and 69.6% in the SC group) reported that the physicians did not express a preference for one medication over another (Table 5).

Not surprising, physicians were by far the most common source of information for both groups, with approximately 90% of patients listing their physician as 1 of the 3 sources from which they learned about their anti-TNFs (Table 6).

Patients receiving infusions reported a higher level of interest in obtaining additional information. On a 5-point scale, 49.5% of patients receiving infusions indicated they were interested or extremely interested in additional information compared with 36.6% of patients receiving SC agents (P = .008).

Discussion
In this study, patients receiving SC anti-TNF agents reported a higher preference for the medication they were currently taking compared with those receiving IV agents. The fact that the preferences among medication users largely corresponded with the route of administration of the drug that patients were taking suggested that they were satisfied with the treatment. The high satisfaction was confirmed by the results of the TSQM version II. The IV users reported higher satisfaction with effectiveness, whereas SC users were more satisfied with convenience.

In addition, a significant portion (46%) of IV patients expressed interest in receiving their medication at home. Many such patients would have several options available, either using a home health agency nurse to receive the infusion at home (<2% of those in the IV group in our study reported actually using that option) or switching to an SC anti-TNF when clinically appropriate.

However, to consider the alternatives available to them, patients need to be informed about different options in terms of agents, administration routes, or locations for treatment. These results demonstrate that although communication with physicians appears to be of high importance in choice of agent and the interest in receiving information about options was substantial, fewer than half of the respondents ever discussed any alternative anti-TNF options with their physician. This highlights a major opportunity for patient education. Such education may be especially important considering that the infusion option has been on the market much longer than other options, and many patients, who usually continue to use an anti-TNF treatment for multiple years, initiated the therapy when alternatives such as infusion administration at home or self-injections were not available.

Although SC administration offers more patient control and convenience by eliminating the need to travel to a physician’s office, it does require a patient to be able to self-inject, and the dosing regimens usually require more frequent administration than IV medications.

Some patients may prefer infusions based on the perception of safety because of the presence of medical personnel, and may find the less frequent dosing regimen more appealing. In fact, the 2014 Danish study of patients with RA reported that the most frequent reason among patients for choosing infusions was a wish for safety; among those preferring SC administration, it was a wish to minimize the time of transportation and treatment.¹⁶

In our study, patients in the IV group were more likely to be in the younger and older age-groups, whereas those in the SC group were more likely to be of working age and to work outside the home. In line with earlier findings, this indicates that lifestyle may play a role in the selection of a specific mode of administration: patients who are working, active, and/or independent are more likely than others to select the option offering better administration flexibility and convenience—the self-administrated anti-TNFs.

Our findings of patients preferring their current route of administration, high treatment satisfaction, and high interest in receiving therapy at home are in line with existing research^14-17; however, we were able to assess a larger and more geographically diverse sample of patients and include multiple indications.

Inclusion of multiple indications allowed us to perform subgroup analysis by condition, revealing that regardless of the condition, the SC treatment option appears to be more preferred (results are available on request). In addition, because our study interviewed respondents in 2012, it provides updated information for the time period in which alternatives to IV infusion treatment have become more frequently used across different indications.

Despite the availability of options that could better address patient preferences, barriers to the more common use of alternatives (in addition to patients’ lack of knowledge) exist in the healthcare system. For example, among both clinicians and payers, the route of administration ranks low in reported importance in the choice of biologics. According to one analysis, clinicians ranked the route of administration fourth after efficacy, safety, and personal experience.20 Payers also ranked the route of administration fourth after efficacy, contracting, and safety.²⁰

In addition, financial incentives can favor the choice of an infusion anti-TNF in both commercial and Medicare markets.^21,22 Infusions are typically covered under medical benefits, which often have more favorable deductibles and out-of-pocket maximums for patients, whereas injections tend to be provided under pharmacy coverage with relatively higher copays or coinsurance.²³

Patient preference is integral to the decision regarding the selection of therapeutic agents and routes of administration, given the potential to increase treatment success. Convenience and ease of administration have been linked to improved adherence to medication regimen.¹⁹ This is an important consideration for anti-TNF therapy, where consistent adherence is very important and is often challenging, with as many as approximately 25% of all users nonadherent to their medication regimen.²⁴

Finally, focuses on quality of life and patient convenience, where similar efficacy and safety for medications have been demonstrated, fall in line with a trend toward the inclusion of quality measures that incorporate patient satisfaction in addition to clinical outcome. For patients using anti-TNF agents, the provision of information on all appropriate agents, routes of administration, and site of infusion service options may engender greater patient trust, sense of shared decision-making, and patient satisfaction.

Limitations
Our survey cooperation rate was 37%. Although the cooperation rate is representative of the rates obtained for similarly structured surveys of health plan members where a concern about member abrasion was implemented by a maximum of 5 contact attempts and no attempts to convert refusals, the results may not be representative of the target population.

The results may not be generalizable to individuals who have noncommercial health insurance or no insurance.

Many patients received only 1 type of therapy, and this would have hindered their ability to provide a fully informed decision on their preferred route of administration.

The questions regarding preference for administration method used a 4-point Likert scale, which might contribute to a bias among patients holding ambiguous attitudes; however, the nonresponse rate for these questions was minimal (ie, <2.5%).

Finally, we did not ask patients about their health status, which might affect preferences.

Conclusions
This survey established that in a commercially insured population of patients using anti-TNF agents, patients receiving SC agents had a higher preference for the medication they were currently taking compared with those receiving infusion therapies. Patients receiving infusions reported higher effectiveness than those using SC agents but lower convenience; however, the magnitudes of the differences were not high, and global satisfaction was similar. A significant proportion of patients in the infusion group expressed interest in receiving their medication at home. These results suggest that the newer options of self-injectable administration and/or home-based infusions, when clinically appropriate, can be attractive alternatives for many patients. Despite that, we found that fewer than 50% of patients ever discussed alternative anti-TNFs with their physician and home-based options were used infrequently. This finding points out a need for greater communication to patients about the options that are available to them.

Acknowledgments
The authors gratefully acknowledge Amanda Rodriguez, HealthCore, for providing valuable input during the questionnaire design phase and for facilitating the data collection. They also thank Jade Dinh, HealthCore, for supporting the data collection process and Cheryl Jones, HealthCore, for her assistance in the preparation of the manuscript. Finally, the authors would like to recognize Curt Le, WellPoint, for his contribution to the definition of the study objectives and design.

Funding Source
Funding for this study was provided by WellPoint. No external source of funding was involved. The authors had complete control over the study planning and results.

Author Disclosure Statement
Ms Sylwestrzak, Dr Liu, Ms Stephenson, and Dr deVries are employees of HealthCore, which is a wholly-owned WellPoint subsidiary; and Dr Ruggieri is an employee of WellPoint.

Ms Sylwestrzak is Research Manager, Payer and Provider Research, HealthCore, Inc.; Dr Liu is Senior Research Analyst, Payer and Provider Research, HealthCore, Inc.; Ms Stephenson is Senior Scientist, Survey-Based Research, HealthCore, Inc.; Dr Ruggieri is Managing Medical Director, Health Care Management, WellPoint, Inc.; Dr DeVries is Director, Payer and Provider Research, HealthCore, Inc.

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