Ameet Sarpatwari, PhD, JD

 To better understand patients’ and pharmacists’ preferences for and experiences with changes in pill appearance (size, shape, color, and markings).

 We conducted independent national surveys of patients 50 years and older taking generic drugs for depression, diabetes, epilepsy, HIV, hyperlipidemia, or hypertension and of licensed pharmacists practicing in chain, franchise, or independent pharmacies. Responses were collected between January and April 2016.

 Of 1000 patient respondents (30% response rate), most reported experiencing changes in pill appearance (51%) and preferred to be notified about them (82%), but less than half recalled being notified (verbally: 36%; via sticker: 45%). Among patients who reported experiencing a change, 12% reported stopping their medication or using it less frequently. Of 710 pharmacist respondents (33% response rate), many reported changes in pill appearance occurring frequently in their pharmacies (47% reported that changes occurred 6 or more times per month) and more than three-fourths reported notifying patients about them often (verbally: 88%; via sticker: 77%).

 Our findings reveal opportunities to improve patients’ experiences with pill appearance changes through better notification practices and patient education.

Conducting separate national surveys of patients and pharmacists, we aimed to better understand their preferences for, experiences with, and responses to changes in generic drug appearance (size, shape, color, and markings).

Most patients reported experiencing changes in pill appearance and preferred to be notified about them, but less than half recalled being notified. Among patients who reported experiencing a change, 12% stopped their medication or used it less frequently.

Most pharmacists reported pill appearance changes occurring frequently in their pharmacies and notifying patients about them often.

These findings reveal opportunities to improve patients’ experiences with pill appearance changes through better notification practices and patient education.

Medication nonadherence occurs when patients do not take their medication as prescribed. About 50% of patients with chronic diseases, such as high blood pressure, high cholesterol, and diabetes, are estimated to be nonadherent.

 Nonadherence can result from factors related to the disease (eg, changes in cognition), medication (eg, adverse effects), patient (eg, forgetfulness), or health system (eg, high drug costs),

 and it has been tied to poorer patient outcomes4 and billions of dollars in US health care spending annually on hospitalizations and other costs associated with disease progression.

One potential contributor to medication nonadherence is lack of consistency in the appearance of a patient’s medication. The FDA requires that generic drugs—which currently comprise about 90% of dispensed prescriptions in the United States

—have the same dosage form, strength, route of administration, intended use, quality, and performance characteristics as their brand-name versions.

 The FDA, however, does not mandate that generic drugs match their brand-name counterparts or each other in terms of physical appearance, including color, shape, size, and markings (text, lines, grooves, or designs). As a result, patients refilling a medication for a chronic disease may experience variations in their pills’ appearance when the generic manufacturer supplying a drug to a pharmacy changes. One study found that 29% of patients initiating treatment with 1 of 4 classes of cardiovascular drugs after hospitalization for a myocardial infarction experienced a change in their pills’ color or shape within 1 year.

 Well-controlled observational analyses have found increased odds of patients stopping or delaying taking essential cardiovascular and antiepileptic drugs when experiencing such changes.

Why patients might respond this way to changes in pill appearance is not known. To explore this question, we conducted national surveys of patients and pharmacists regarding their preferences for, experiences with, and perceptions and responses to changes in generic drug appearance.

We conducted 2 independent national surveys of patients and pharmacists with assistance from Nielsen Healthcare. The Office of Management and Budget approved the study under the Paperwork Reduction Act of 1995, assigning it the control number 0910-0801. The Brigham and Women’s Hospital Institutional Review Board also approved this study. All analyses were performed using SAS version 9.4 (SAS Institute).

Eligibility for the patient survey was restricted to patients 50 years and older taking a generic medication for depression, diabetes, epilepsy, HIV, hyperlipidemia, or hypertension. These conditions were chosen to capture a wide range of chronic diseases. The age criterion was included to increase the likelihood that contacted individuals—recruited through phone sampling—would have 1 of the listed chronic diseases.

A total of 16,243 landline and cell phone numbers were identified from Survey Sampling International’s Directory Listed Household Sample and Wireless LITe database. From this sample, 6 pretests were conducted in January 2016 that resulted in minor modifications to the survey instrument, such as grammatical fixes and adjustments for clarity. Phone interviews took place between February and April 2016, lasted an average of 18 minutes, and concluded once the target of 1000 respondents was reached.

The patient survey was administered using a 56-question, closed-field instrument (

]). We first inquired about reliance on and preference for consistent pill appearance, asking patients whether they used pill appearance to make sure they took the correct medication and whether they preferred their pills to retain the same color, shape, size, or markings upon medication refill. We then asked patients how often they experienced a change in their pills’ appearance, whether their pharmacist notified them about the change, and what their preference was for being notified when their pills’ appearance changes. Other questions addressed patients’ actions in response to changes in their pills’ appearance. Finally, we collected information about patients’ sex, age, race, education, income, and Census region. Reliance, preference, and perception questions were assessed using Likert scales.

The pharmacist survey targeted licensed pharmacists practicing in independent, franchise, and chain settings in the United States. We randomly selected 2161 practicing pharmacists believed to be practicing in such settings from a master file of more than 100,000 pharmacists in more than 50,000 pharmacies maintained by the data vendor SK&A. The number was chosen based on power calculations using simulated response distributions and an assumed 50% response rate.

Each selected pharmacist was sent a postcard alert and a survey mailing between January and April 2016 that included a paper survey, a URL for optional online completion of the survey, a prepaid return envelope, and a $5 cash honorarium. Nonresponders received a reminder letter and a second packet without the honorarium.

The pharmacist survey was self-administered using an instrument with 23 closed-field questions (

). The survey was pretested in a convenience sample of 5 practicing pharmacists, with small adjustments made for question clarity based on their responses. We asked pharmacists about their perceptions of generic drug safety and effectiveness, followed by their preferences for consistent pill appearance. We then asked how frequently pharmacists observed generic pill appearance changes in their pharmacies and what they generally did to alert patients when such changes occurred. Other questions focused on reports that pharmacists received from patients in response to pill appearance changes, such as a belief that the wrong medication had been given. Finally, we collected information on pharmacists’ sex, race, title, business type, number of years in practice, number of prescriptions filled per day, and source(s) of drug information. As with the patient survey, preference and perception questions were assessed using Likert scales.

The response rate for the patient survey was calculated using the American Association of Public Opinion Research’s second standard definition.

 Multivariable logistic regression modeling was used to examine predictors of patient preferences for pill appearance. For this model, a constructed outcome variable was derived based on the question of whether patients preferred the size, shape, color, or markings of their pills to remain the same, grouping patients who responded “definitely” or “probably” to any of these 4 questions vs patients who responded “no preference,” “definitely not,” or “probably not” to all questions. Multivariable logistic modeling was also used to examine predictors of patients who reported using a medication less frequently or stopping a medication following a pill appearance change. For each model, the covariates were sex, race (white/nonwhite), age (50-57, 58-65, ≥ 66 years), medical condition (hypertension, hyperlipidemia, diabetes, depression, epilepsy, HIV, multiple), region (East, Midwest, South, West), education (high school, college, graduate), and income (<$50,000, $50,000-<$100,000, ≥$100,000).

Multivariable ordinal logistic regression modeling was used to examine predictors of pharmacist preferences for generic pill appearance consistency, grouping pharmacists who responded “much prefer” or “somewhat prefer,” “no preference,” and “somewhat not prefer” or “much not prefer.” The frequency of observing generic pill appearance changes, frequency of being notified about generic pill appearance changes, likelihood of notifying patients verbally in person or on the phone about pill appearance changes, and likelihood of notifying patients via sticker on the pill bottle about pill appearance changes were also modeled using ordinal logistic regression but without any grouping of response categories. Covariates in the models were pharmacy type (chain, nonchain), years in practice (continuous), position (owner/chief pharmacist, staff/other), and pharmacy prescription dispensing volume (≤ 200 prescriptions per day, > 200 prescriptions per day).

A total of 1000 patients (30% response rate) and 710 pharmacists (33% response rate) completed the surveys (

). Of the patient respondents, 61% were women, 79% were white, and 57% were 66 years or older. Of the pharmacist respondents, 47% were women, 80% were white, and 56% identified as a staff pharmacist. These percentages are comparable with those nationally.

 About half of respondents filled more than 200 prescriptions per day (52%), and about one-third practiced in an independent pharmacy (38%) and reported practicing for 30 years or longer (34%). Although we targeted pharmacists in independent, franchise, and chain settings, 10% of respondents reported practicing in other settings, most often hospital-associated outpatient pharmacies.

Patients’ and Pharmacists’ Pill Appearance Preferences

Most patients preferred to have a consistent pill appearance. More than half of patients “definitely” or “probably” preferred their prescription refills to have the same color (63%), size (68%), shape (63%), and markings (55%) (

). In multivariable modeling, only race was associated with a preference for consistent pill appearance (

). Nonwhite patients were more likely to prefer consistent pill appearance (odds ratio [OR], 2.58; 95% CI, 1.52-4.38).

In contrast with patients, most pharmacists (54%) had no preference for consistent pill appearance of generic drugs when dispensing, and 12% preferred not to dispense generic drugs with the same appearance (Table 2). Multivariable analysis revealed that pharmacists who reported practicing for fewer years were more likely to prefer pill appearance consistency (OR per 10 years of practice, 0.78; 95% CI, 0.69-0.88) (

About half of patients (51%) reported receiving a prescription refill in which their pills’ appearance changed in the last year and, of those patients, about half (53%) reported that it happened 2 or more times (Table 2). Patients reported that pill color was the characteristic that changed most frequently (68%), followed by shape (46%), size (42%), and markings (20%).

More than four-fifths of pharmacists reported that their pharmacy changed generic drug manufacturers with resulting changes in pill appearance at least twice per month: never or once per month (15%), 2 to 5 times per month (38%), 6 to 15 times per month (25%), and more than 15 times per month (22%) (Table 2). In multivariable modeling, chain/franchise pharmacies were more likely than independent pharmacies to experience such changes (OR, 1.57; 95% CI, 1.11–2.22) (Table 4).

A majority of pharmacists reported that they were either “never” (28%) or “rarely” (28%) alerted when their pharmacy, distributor, or wholesaler changed suppliers for generic pills with a different appearance (Table 2). In multivariable modeling, only pharmacy type was associated with such notification, with pharmacists working at a chain/franchise pharmacy having a greater likelihood than pharmacists in independent pharmacies of being alerted when pill appearance changes occur (OR, 1.62; 95% CI, 1.15-2.27) (Table 4).

Patient and Pharmacist Notification Preferences, Experiences, and Practices

Patients overwhelmingly reported that they “definitely” (66%) or “probably” (16%) desired to be notified of a change in their pills’ appearance by their pharmacist and that they preferred being notified verbally (45%) over a sticker on the prescription bottle (36%) (Table 2). Among patients reporting experiencing a change in pill appearance during the prior year, 36% reported that pharmacists notified them about the change verbally, whereas 45% reported being notified with a sticker on the bottle.

When pharmacists were asked about their notification practices when pill appearance changed, most pharmacists reported that they “almost always” (47%) or “commonly” (30%) notified patients verbally (Table 2). A large majority of pharmacists also reported that they “almost always” (73%) or “commonly” (15%) notified patients using a sticker on the prescription bottle. Most pharmacists reported “never” (55%) logging an incident report when a patient complained about a change in pill appearance and “rarely” (27%) or “never” (34%) leaving a note in the patient’s pharmacy record indicating that a change occurred. Multivariable analysis revealed that pharmacists working in pharmacies filling more than 200 prescriptions per day were more likely to notify patients about a change in pill appearance verbally (OR, 1.78; 95% CI, 1.34-2.38) and via a sticker on the pill bottle (OR, 1.65; 95% CI, 1.17-2.33) (Table 4).

Patient Responses to and Beliefs About Pill Appearance Changes

Among patients reporting that they experienced a pill appearance change, almost one-third (29%) reported thinking that they received the wrong pill (Table 2). About 1 in 8 patients reported changing their medication use, either using the pills less frequently (8%) or stopping their use completely (4%). Multivariable analysis found that nonwhite patients were more likely than white patients to use their pills less frequently or stop completely when they experienced a change in their pills’ appearance (OR, 2.89; 95% CI, 1.42-5.85) (Table 3).

Other actions that patients reported taking in response to a change in their medication’s appearance included asking their pharmacist (35%) or physician (9%) about the change (Table 3). Of those patients who reported asking their pharmacist or physician, 97% reported that their pharmacists alleviated their concerns, and 84% reported that their physician alleviated their concerns.

In national surveys, we found that most patients preferred the appearance of their generic pills to remain the same, with some patients reporting using their medication less frequently or stopping it completely when such changed occurred. Pharmacists reported that changes in generic pill appearance happened frequently in their practice, but that they were often not alerted when such changes occurred. Far more pharmacists reported notifying patients about generic pill appearance changes, either verbally or with a sticker on the bottle, than patients recalled being notified by pharmacists.

Our patient findings align well with those of a separate survey we conducted of commercially insured patients taking generic medication indicated for 1 of 4 chronic diseases (depression, epilepsy, hyperlipidemia, and hypertension) who had recently experienced a change in the appearance of their pills.16 In this study, most respondents also reported wanting their pills to remain the same color (72%), size (75%), and shape (71%). Similarly, more than three-fourths of respondents (86%) also reported wanting to be notified when their pills changed appearance, and a minority likewise recalled their pharmacist informing them of the change (verbal: 19%; via a sticker on the pill bottle: 30%). Finally, the same percentage of respondents (8%) reported adjusting their medication use following the change. Combined, these findings suggest that many patients rely on pill appearance to make sure they are taking the correct medication and that changes in appearance may cause confusion, prompting some patients to stop taking their medication. This may be particularly important among elderly patients taking multiple medications for chronic diseases. We are unaware of prior published surveys about the preferences of and experiences with pill appearance changes among pharmacists.

Our study reveals opportunities to improve patient and pharmacist experiences when pill appearance changes: through patient education about the potential for pill appearance changes for generic medication, along with better notification practices and knowledge transfer when such changes occur. Because many pharmacists reported rarely or never being alerted of such changes, creation and widescale adoption of an automated point-of-dispensing system that alerts pharmacists when a patient’s generic pill has changed appearance and indicates what that change is (eg, size, shape, color, and/or markings) would be helpful.

The observed disconnect between pharmacists reporting notifying patients about generic pill appearance changes and patients reporting not recalling being notified, meanwhile, suggests that the mode of communication between pharmacists and patients is important. Pharmacists most commonly reported notifying patients using a sticker on the bottle regardless of their practice type. Patients, however, reported preferring a verbal notification and may not have looked closely at their pill bottles.

Finally, some patients—notably, nonwhite patients—were more likely to report using their medication less frequently or stopping completely when a generic pill appearance change occurred. It is unclear why this may be the case, highlighting an avenue for further investigation in addition to populations for targeted intervention.

There are limitations to our study relevant to the disconnect identified between patients and pharmacists. The surveys were conducted independently, meaning that the patients surveyed did not receive prescriptions dispensed by the pharmacists surveyed. Like all surveys, our study was also subject to possible participation, recall, and response biases. Patients who were counseled by their pharmacist may have misremembered the conversation, and patients who had issues with changes in their pills’ appearance may have been more likely to participate. Similarly, patients with HIV may been reluctant to report having the condition. Survey questions for patients and pharmacists, meanwhile, were not phrased identically and may have been interpreted differently. For example, patients may have interpreted the question “When your pill changed in appearance, as best you recall, did your pharmacist talk to you about the change, in person or on the phone?” literally, thinking that if someone other than the pharmacist (eg, pharmacy technician) talked to them, then they were not notified. By contrast, pharmacists may have had a more general interpretation of their question asking about prescription refill practices when pill appearance changes, thinking that if a member of the pharmacy team, such as a pharmacy intern, counseled the patient, then that was sufficient and reported accordingly.

Additional limitations to our study warrant noting. First, our patient findings were limited to older patients with 6 specific chronic conditions and may not be generalizable to younger patients or those with other diseases. Second, given our response rates and sampling frames, it is possible that our results are not generalizable to all segments of the target populations. Third, our surveys were designed to explore experiences with changes in pill appearance but could not assess the clinical appropriateness of the change. Finally, our ascertainment of patient sex based on voice could have been inaccurate.

There were also several strengths to our investigation. Both patients and pharmacists were surveyed—as opposed to one group or the other—about similar topics. The surveys were national in scope, and the number of respondents for both was large.

Our study indicates that most patients report not being notified when they experience changes in pill appearance during a medication refill even though pharmacists report that these changes happen frequently in the pharmacy. A disconnect exists between patients’ reported experiences and pharmacists’ reported practices regarding notification when that change does occur, with some patients altering their medication use in response. Improving patient education about potential pill appearance changes and notification practices around the time such changes occur may improve the experiences of both patients and pharmacists.

 Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (REB, ASK, JJG, ZL, AS), Boston, MA; Center for Bioethics and Humanities at the University of Colorado (EGC), Aurora, CO; Office of Generic Drugs Surveillance and Epidemiology, Center for Drug Evaluation and Research, FDA (SKD), Silver Spring, MD; Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA (WJ), Silver Spring, MD.

 This work was supported by a contract from the FDA Office of Generic Drugs and Office of Chief Scientist (HHSF223201310232C).

 Dr Barenie was a consultant to Alosa Health for unrelated work. Dr Gagne was a consultant to Optum, Inc, for unrelated work and received salary support from grants from Eli Lilly and Company and Novartis Pharmaceuticals Corporation to the Brigham and Women’s Hospital for unrelated work. Dr Campbell serves as a paid expert on law cases related to conflicts of interest in medicine. Dr Dutcher and Dr Jiang are employees of the FDA, which funded the work described in this manuscript. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (ASK, JJG, EGC, SKD, WJ, AS); acquisition of data (ASK, EGC, AS); analysis and interpretation of data (REB, ASK, JJG, ZL, SKD, WJ, AS); drafting of the manuscript (REB, ZL, AS); critical revision of the manuscript for important intellectual content (REB, ASK, JJG, EGC, SKD, AS); statistical analysis (ZL, AS); obtaining funding (ASK, AS); administrative, technical, or logistic support (WJ, AS); and supervision (JJG, AS).

 Rachel E. Barenie, PharmD, JD, MPH, Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120. Email: rbarenie@bwh.harvard.edu.

1. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. 

. 2002;288(4):462-467. doi:10.1001/jama.288.4.462

2. Oung AB, Kosirog E, Chaves B, Brunner J, Saseen JJ. Evaluation of medication adherence in chronic disease at a federally qualified health center. 

. 2017;8(8-9):113-120. doi:10.1177/2040622317714966

3. McLeroy KR, Bibeau D, Steckler A, Glanz K. An ecological perspective on health promotion programs. 

. 1988;15(4):351-377. doi:10.1177/109019818801500401

4. Overcoming barriers to medication adherence for chronic diseases. CDC. February 21, 2017. Accessed November 6, 2019. https://www.cdc.gov/grand-rounds/pp/2017/20170221-presentation-medication-adherence-H.pdf

5. Medication adherence in America: a national report. National Community Pharmacists Association. 2013. Accessed November 6, 2019. http://www.ncpa.co/adherence/AdherenceReportCard_Abridged.pdf

6. Avoidable costs in U.S. healthcare: the $200 billion opportunity from using medicines more responsibly. IMS Institute for Healthcare Informatics. June 2013. Accessed November 6, 2019. http://offers.premierinc.com/rs/381-NBB-525/images/Avoidable_Costs_in%20_US_Healthcare-IHII_AvoidableCosts_2013%5B1%5D.pdf

7. Jha AK, Aubert RE, Yao J, Teagarden JR, Epstein RS. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. 

. 2012;31(8):1836-1846. doi:10.1377/hlthaff.2011.1198

8. Generic drug access & savings in the U.S.: access in jeopardy. Association for Accessible Medicines. 2018. Accessed November 6, 2019. https://accessiblemeds.org/sites/default/files/2018_aam_generic_drug_access_and_savings_report.pdf

9. Applications for FDA Approval to Market a New Drug. 21 CFR §314.3, 320 (2019).

10. Kesselheim AS, Bykov K, Avorn J, Tong A, Doherty M, Choudhry NK. Burden of changes in pill appearance for patients receiving generic cardiovascular medications after myocardial infarction: cohort and nested case-control studies. 

. 2014;161(2):96-103. doi:10.7326/M13-2381

11. Kesselheim AS, Misono AS, Shrank WH, et al. Variations in pill appearance of antiepileptic drugs and the risk of nonadherence. 

. 2013;173(3):202-208. doi:10.1001/2013.jamainternmed.997

12. Buttorff C, Ruder R, Bauman M. Multiple chronic conditions in the United States. RAND Corporation. 2017. Accessed November 6, 2019. https://www.rand.org/content/dam/rand/pubs/tools/TL200/TL221/RAND_TL221.pdf

13. Standard definitions: final dispositions of case codes and outcome rates for surveys. American Association for Public Opinion Research. 2016. Accessed November 6, 2019. https://www.aapor.org/AAPOR_Main/media/publications/Standard-Definitions20169theditionfinal.pdf

14. 2014 national pharmacist workforce survey. American Association of Colleges of Pharmacy. April 8, 2015. Accessed November 6, 2019. https://www.aacp.org/sites/default/files/
executivesummaryfromthenationalpharmacistworkforcestudy2014.pdf

15. Pharmacists. Data USA. Accessed November 6, 2019. https://datausa.io/profile/soc/291051/#demographics

16. Sarpatwari A, Gagne JJ, Lu Z, et al. A survey of patients’ perceptions of pill appearance and responses to changes in appearance for four chronic disease medications. 

. 2019;34(3):420-428. doi:10.1007/s11606-018-4791-1

Articles

Changes in generic drug appearance occur often. Patients’ and pharmacists’ responses to those changes vary, with some patients stopping their medication or using it less.

Ameet Sarpatwari, PhD, JD

Articles

Preferences for and Experiences With Pill Appearance Changes: National Surveys of Patients and Pharmacists