PONE-D-23-00503Pharmacy and Neighborhood-Level Variation in Price of Diabetes Medications in the United StatesPLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study aimed to examine pharmacy and neighborhood factors associated with cost variation for diabetes drugs in the US using all-payer US pharmacy data from 45,874 chain and independent pharmacies reflecting 7,073,909 deidentified claims. The authors reported that cash prices for diabetes medications in the US can vary considerably and that the greatest degree of price variation occurs in non-insulin generic therapies. Overall, it’s topically interesting and timely as the authors properly stated that “high medication costs place a significant burden on the health system and represent an important barrier to broad and equitable prescription drug access.” The reviewer has four main comments regarding conceptualization, methodology, interpretation of the results, and limitations.

1. Conceptualization: the authors stated that “The U&C price is the price charged to a customer in the absence of insurance or negotiated discount. Although most customers have prescription medication coverage and do not pay the U&C price, the U&C price is the most visible price at the retail level and impacts those lacking insurance. “(Methods, Page 4) Conceptually, the U&C price is not the price a consumer pays for the medication if the consumer has health insurance, and most US consumers have certain insurance coverage such as Medicare, Medicaid, and private insurance. Hence, the “price” the authors referred to was not the actual price most consumers were paying, and its implication to practice and policy is unclear. A well-thought-out introduction of the U&C price in the light of transactions among the wholesaler, pharmacy chains, consumers with or without insurance is needed to help the readers to better understand the relevance and significance of the study.

2. Methodology: the authors stated that “A generalized linear model with gamma distribution and log link function was constructed for each drug group and the models were stratified by pharmacy type (independent or chain) (Methods, Page 5). Were family (gamma) and link (log) tests performed to determine the appropriateness of the gamma distribution and log link function? How did the distribution of cash price-per-unit (PPU) look like? Some tables/figures would be informative to show the distribution of the outcome measure the authors had in the analysis by drugs.

3. Interpretation of the results: the authors stated that “We then identified pharmacy and neighborhood factors associated with drug price variation” using the generalized linear model (Methods, Page 5). The authors also stated that “Neighborhood variables sourced from the 2019 American Community Survey included mean household income (normalized), insurance coverage (Medicare, Medicaid, other insurance, no insurance coverage), race/ethnicity (Hispanic/Latino), and mean-to-median household income ratio.” In Results, the analysis was then interpreted as “Average proportion covered by commercial insurance was 53%, followed by Medicaid (18%), Medicare (13%), other insurance (8%) and no insurance (8%).” (Results, Page 6). Was this insurance coverage derived from the ACS or the pharmacy data? Please clarify. Please also clarify the unit of analysis, for example, how the neighborhood was defined, how many neighborhoods were covered in this data, and the reference groups in the results, for example, when the authors stated that “Chain pharmacies were likely to have higher prices in neighborhoods with greater proportions of high-income residents (+7.9%), urban housing units (+8.4%), and Medicaid beneficiaries (+17.3%), and had lower prices in neighborhoods with greater proportion of people without insurance (-11.2%),” (Results, Page 7), please clarify the reference groups for each of these comparisons, and where those coefficients came from, their associated p-values, for example, was this +7.9% associated with each unit increase in the household income by ACS, if so, what is the unit increase of household income?

4. Limitation: While the authors stated that “Pharmacy-level price variation was greater for non-insulin generic therapies than insulins or brand name therapies. Chain pharmacies had both lower prices and lesser variation compared with independent pharmacies”, (Results, Abstract), their implication to practice and policy was unclear given the generic drugs had much lower acquisition costs and cash prices, hence, the cost burden to those customers who do not have health insurance is much smaller. In addition, since the U&C price is not the actual price most consumers are paying, it would be more appropriate to span out the “usual and customary prices” or “cash price” in the title to clarify.

Reviewer #2: I have also uploaded my comments: 1. Authors gave a good rationale for the study- differences in prices could affect those without insurance, other cash paying patients and possibly those with deductibles. I have some comments for clarification and/or consideration.

2. Can you give a reference for the definition of U&C, I saw a reference by Joey Mattingly that the law 42C.F.R &447.512(b) requires pharmacies to report the U&C when submitting pharmacy claims for both Rx and OTC but not cash paying sales?

3. The authors divided the diabetic medications into 3 groups: insulins, non-insulin generics, and brand name non-insulins. What about brand name drugs that are not GLP1s, SGLTs and DPP4s, such as Glucophage? Or brand name insulins? Were they eliminated from the study?

4. I think cash PPU is a poor measure to compare these drugs since collectively, they are given at different doses and frequencies (some are once a week, twice a day etc) why don’t you ‘cost per day’? Or by class, such as generic biguanides, brand name biguanides, GLP1s etc? The variability will be significantly different.

5. Can you define chain pharmacies? Do you mean stand-alone pharmacies like CVS or does it include supermarket chains like Walmart? These 2 chain-types have different pricing strategies and should be treated differently.

6. Can you add the rationale for choosing cutoff for extreme outliers at 10X the median?

7. Do you have a reference for how you treated variability across neighborhoods on page 5?

8. Typo: Tablet instead of table (page 5 last line)

9. Please use generic names instead of brand names like Lantus and Jardiance.

10. Because of how broadly you classified the drugs into 3 groups- it weakens the relevance of the findings. It will be better to treat the drugs by class and that will be meaningful for prescribers.

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Reviewer #1: No

Reviewer #2: No

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Submitted filename: Reviewers PLOS ONE diabetes.docx

Pharmacy and Neighborhood-Level Variation in Cash Price of Diabetes Medications in the United States

PONE-D-23-00503R1

Dear Dr. Warraich,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Mihajlo Jakovljevic, MD, PhD, MAE

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have been responsive to reviewers' comments. The manuscript is stronger with greater clarity.

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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