INTRODUCTION

Systematic Literature Review of Compliance and Persistence Programs in Inflammation and Immunology

Chakkarin Burudpakdee1, Satyin Kaura2, Smeet Gala1, Merena Navavaty1, Zeba M. Khan2 1Market Access Solutions, LLC., Raritan, NJ; 2Celgene Corporation, Summit, NJ

Patient compliance and persistence to treatment are important for effective disease management, especially in chronic diseases that may become more severe over time such as autoimmune and inflammatory conditions.

Prevalence rates of autoimmune diseases range between 5 to 500 per 100,000.1 In the US, over 7 million individuals suffer from inflammatory rheumatic diseases which are the most severe among inflammatory diseases.2

Compliance (i.e. adherence) refers to the act of conforming to recommendations made by a provider with respect to timing, dose, and frequency of administration. Persistence is defined as the duration of time from initiation to discontinuation of therapy.3

Medication compliance has been shown to be low in immunology and inflammation (I&I) diseases.4-6

Non-compliance rates in patients have been high, ranging from 43% to 72% in inflammatory bowel disease,7 40% in psoriasis,8 and 30% to 80% in rheumatoid arthritis.9,10

A number of recent programs have been developed to improve medication compliance and persistence by using interventions focused on educational,5,11,12 behavioral6,13 and multimodal strategies.14

To create a successful patient program, a comprehensive understanding of effective patient compliance and persistence programs is needed.

International Health Economics and Outcomes Research (ISPOR) 19TH Annual International Meeting, Montreal, QC, Canada, May 31 – June 4, 2014

To understand what interventions have been successful in improving patient compliance and persistence in the I&I therapeutic area To identify key learnings from successful programs

OBJECTIVES

REFERENCES

PHS82

PubMed, conference proceedings and grey literature were searched for relevant articles published between January 2008 and September 2013, in English, German, Spanish, Italian or French languages. Primary search and MeSH terms used were I&I disease

related; secondary search and MeSH terms used were compliance and persistence programs related. Additionally, 44 conferences were searched for compliance

and persistence studies in the I&I therapeutic area. A total of 3,637 title and abstracts were screened for

eligibility by two researchers, and discrepancies were resolved by a third researcher. Any undetermined titles and abstracts were reviewed via full-text screening. Studies assessing compliance and persistence after

implementation of a patient program in I&I disease area were included in the final review.

METHODS

Tailored patient preference - ulcerative colitis (UK)15 Compliance for Intervention (I) vs Control (C) (12 months): 76% vs 32% (p = 0.001)

Intervention – Patients received one-on-one patient education, motivational session, identification of barriers and strategies to overcome them, free choice of up to 3 compliance improving interventions such as reminder charts, electronic pill box, alarms, and finally a follow-up call after a month. Control – Patients received standard pharmacotherapy.

Web-based education program - inflammatory bowel disease (Denmark and Ireland)12

Denmark - Compliance for I vs C (12 months): 73% vs 42% (p = 0.005) Ireland - Compliance for I vs C (12 months): 73% vs 29% (p = 0.03)

Intervention – Patients and relatives received a presentation covering disease-related topics. Using a web-based program patients could ask their web-doctor questions directly using email, text, or call. After 6 and 12 months, all patients were asked to fill in a compliance questionnaire. Control – Patients received conventional treatment and follow-up in the out-patient clinic for 12 months.

Pharmacy based management - osteoporosis (USA)16 Compliance for I vs C (6 months): 46% vs 28% (p = 0.007) Persistence for I vs C (6 months): 54% vs 45% (p = 0.19)

Intervention – Pharmacist reviewed patients’ medical records and developed a therapeutic plan involving recommendations for screening, initiation of osteoporosis therapy, and calcium and vitamin supplementation, which was then approved by the primary care provider (PCP) before implementing; pharmacist followed up with patients for 6 months. Control – One centrally located registered nurse reviewed medical records and assessed appropriateness of either screening or

initiation of therapy, which was then assessed by a PCP before implementing.

Group-based educational program - osteoporosis (Denmark)11

Compliance for I vs C (24 months): 92% vs 80% (p = 0.006)

Intervention – Groups of patients received education by a multidisciplinary team and the program was adjusted to the individual’s background and needs; the team focused on patients’ everyday life and supported them in making choices to handle the disease on a daily basis. Participants were invited for a brush-up session after a year and assessment after two years. Control - Patients continued with osteoporosis therapy as prescribed.

Self-injection training and telephone follow-up program - osteoporosis (Italy)17

Persistence for I vs C (18 months): 86% vs 77% (p = 0.006)

Intervention – Nurses trained patients on self-injection and gave new drug pens to patients every 2 months; this guaranteed the surveillance of compliance. Nurses called patients to help resolve any possible issues, scheduled the next visit, and, if applicable, collected adverse events information, dates, and reasons for treatment discontinuation. Control - Patients in the control group were not trained on self-injection and would voluntarily visit their nurse every 6 months to review

their treatment plan. Every 2 months they had to come to the center for their drug pen.

Pharmaceutical care and counselling - osteoporosis (Malaysia)18

Pill count for I vs C (6 months): 98.8 vs 97.0 (p = 0.028) Pill count for I vs C (12 months): 97.7 vs 96.5 (p = 0.322) Persistence for I vs C (12 months): 87.0% vs 89.8% (p = 0.481)

All participants were dispensed 3 months of bisphosphonate; instructed on how to take their medications and were requested to record the date they took their bisphosphonates and to bring back all remaining medications at their next visit for a pill count. Intervention – Participants received a “counselling package” explaining various aspects of the disease and goals of therapy;

pharmacists provided verbal counselling on the disease and conducted monthly follow-up calls for the first 6 months, then every 3 months until month 12. Control - Participants received no counselling.

DTM Program - rheumatoid arthritis (USA)19 Compliance (proportion of days covered) for I vs C (8 months): 0.89 vs 0.60 (p < 0.001)

Intervention – Participants who filled a prescription for an injectable rheumatoid arthritis medication through the Pharmacy Benefit Management’s (PBM) specialty pharmacy and enrolled in the DTM program were given refill reminders, mailed educational materials, and had 24-hour access to pharmacists; telephone consultation was provided by clinicians to improve self-management skills. Control – Patients who filled their prescription at a community pharmacy.

Specialty care management - multiple sclerosis (USA)20

Compliance (medication possession ratio) for I vs C (12 months): 0.86 vs 0.64 (p < 0.001) Persistence for I vs C (12 months): 306.10 days vs 246.90 days (p < 0.001)

Intervention – Medication was mailed to patients with disease-specific educational material; nurses made assessment calls and follow-up calls and refill reminders calls. Control - Patients who filled their prescription at a community pharmacy.

DTM Program - multiple sclerosis (USA)4 Compliance (medication possession ratio) for I vs C (8 months): 0.92 vs 0.86 (p < 0.001) Persistence for I vs C (8 months): 220 days vs 177 days (p < 0.01)

Intervention – Patients received telephone consultations, care plan mailings and educational materials. The clinician assessed patient’s knowledge and health concerns, provided education on core topics, developed a personalized care plan summarizing the telephonic consultation and sent it to the patient and the prescriber. Patients also received monthly educational mailings specific to MS for 6 months. Control – Patients who filled their prescription at a retail pharmacy.

Table 1. Summary of Successful Interventions Resulting in Significant Improvement in Medication Compliance and / or Persistence

Of the 9 studies included in the literature review, 4 studies were conducted in the USA, 1 each in the UK, Denmark, Italy and Malaysia, and 1 multinational (Denmark and Ireland). The review included 4 studies in osteoporosis, 2 in multiple

sclerosis, 1 each in ulcerative colitis, inflammatory bowel disease, and rheumatoid arthritis. The designs of the studies in the review included

randomized controlled trials (n = 4), retrospective database studies (n = 4), and 1 study with unspecified study design. Compliance was measured in 8 studies and persistence

was measured in 5 studies; 4 studies measured both. Compliance significantly improved in interventions that

used tailored patient preferences, web-based education, pharmacy-based management, pharmaceutical care and counselling, disease therapy management (DTM), and speciality care management. Persistence significantly improved in interventions that

used self-injection training and follow-up, speciality care management, and DTM; in contrast, improvements were not significant in interventions using pharmacy-based management or pharmaceutical care and counselling.

LIMITATIONS

Since no standard unit of compliance measurement was used across studies, it was not possible to make a direct comparison between studies.

Some studies included only a specific sample population (for example, patients with internet access, access to phone and emails), therefore, findings may not be generalizable to all patient populations.

STRENGTHS This is the first systematic global review that provides an

assessment of interventions aimed at improving compliance and persistence in the I&I therapeutic area.

This review was comprehensive and included peer-reviewed journals, conferences (e.g. AcademyHealth, American Academy of Dermatology, ISPOR) and grey literature that reported findings from compliance and persistence programs in I&I.

CONCLUSIONS

Based on the reviewed literature, the following strategies were successful in improving patient compliance and persistence • Patient education

- One-on-one tailored counseling on disease and treatment - Web-based or text messaging communication with doctors to answer treatment questions - Group-based motivational and support program

• Disease management - Counselling by pharmacist with regular follow-up calls - Materials and live support to develop patients’ self management skills of disease or therapy

• Patient reminders - Telephone call and / or email reminders to fill and pick up prescriptions

Patient empowerment, motivation, convenience and assistance are the core of effective patient programs. An effective approach to improve compliance and persistence could be developed using an evidence-based approach by combining the

strategies of successful interventions in I&I.

Iden

tify

Scr

een

Elig

ible

In

clud

e

PubMed (Jan 2008-Sept 2013)

Conference proceedings and grey literature (Jan

2008-Sept 2013)

Records screened

(n = 3,637)

Abstracts excluded (n = 3,571) 1.Non-EU5 languages (n = 93) 2.Not compliance / persistence

related (n = 2,854) 3.Not a patient program (n =

572) 4.Not I&I therapeutic area (n =

52)

Full-text articles excluded (n = 57) 1.Cross referencing (n = 9) 2.Not compliance / persistence

or patient program (n = 27) 3.Full-text not available (n = 2) 4.Undetermined or non-

significant improvement in compliance / persistence (n = 19)

Studies included in qualitative

review (n = 9)

Full-text articles

assessed for eligibility (n = 66)

Figure 1. Flow Diagram of Systematic Literature Search

RESULTS

A total of 60 full-text articles and 7 conference abstracts were assessed for eligibility, of which 9 were included. A PRISMA flow diagram was employed for study selection

and inclusion (Figure 1).

RESULTS (CONT’D)

1. Cooper GS, Stroehla BC. Autoimmunity reviews. 2003;2(3):119-125

2. Helmick CG et al. Arthritis & Rheumatism. 2008;58(1):15-25

3. Cramer JA et al. Value in health. 2008;11(1):44-7

4. Stockl KM et al. The American journal of managed care. Feb 2010;16(2):139-144

5. Montori VM et al. The American journal of medicine. Jun 2011;124(6):549-556.

6. Hommel KA et al. Journal of pediatric gastroenterology and nutrition. Oct 2011;53(4):435-439.

7. Hawthorne A et al. Alimentary pharmacology & therapeutics. 2008;27(12):1157-1166.

8. Richards H et al. Journal of the European Academy of Dermatology and Venereology. 2006;20(4):370-379.

9. van den Bemt B et al. Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Review of Clinical Immunology. May 2012; 8.4: 337-351

10. Barton JL et al. The Journal of rheumatology. Dec 2009;36(12):2635-2641.

11. Nielsen D et al. Patient education and counseling. Nov 2010;81(2):155-160.

12. Elkjaer M et al. Gut. Dec 2010;59(12):1652-1661.

13. Moss AC et al. Journal of Crohn's & colitis. Jun 2010;4(2):171-175.

14. Kripalani S et al. Archives of internal medicine. 2007;167(6):540.

15. Moshkovska T et al. Inflammatory bowel diseases. Sep 2011;17(9):1874-1881.

16. Heilmann RM et al. American journal of health-system pharmacy : AJHP Mar 15 2012;69(6):504-509.

17. Tamone C et al. Calcified tissue international. Apr 2012;90(4):272-278.

18. Lai PS et al. Journal of clinical pharmacy and therapeutics. Oct 2011;36(5):557-567.

19. Stockl KM et al. Journal of managed care pharmacy : JMCP. Oct 2010;16(8):593-604.

20. Tan H et al. Multiple sclerosis (Houndmills, Basingstoke, England). Aug 2010;16(8):956-963.