PONE-D-21-09579

Providers’ Mediating Role for Medication Adherence among Cancer Survivors

PLOS ONE

Dear Dr. Trogdon,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please pay special attention to the concerns raised by reviewer 2 on the discussion

Please submit your revised manuscript by Jul 12 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ilana Graetz

Academic Editor

PLOS ONE

Journal Requirements:

1) Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

2) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

3) In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including the date range (month and year) during which patients' medical records were accessed.

4)  We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5)  We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

6) Thank you for stating the following in the Competing Interests section:

[Dr. Lund’s spouse is a full-time, paid employee of GlaxoSmithKline who also holds

stock in the amount of approximately $42,000. Dr. Lund also receives unrelated grant

funding paid to her institution from AbbVie. Dr. Wheeler receives unrelated grant

funding paid to her institution from Pfizer. All other co-authors have no potential

competing interests to report.].

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

7) Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

[Note: HTML markup is below. Please do not edit.]

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: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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

**********

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 is a mediation analysis of the provider team’s role in changes to chronic condition medication adherence among cancer survivors. The study topic is of interest from both clinical and policy perspective. Further, the study has a reasonable methodology, although has limitations in terms of using SEER-Medicare data and relying on pharmacy refills as a measure of adherence. There are few minor comments regarding this study:

1- It is understandable that the authors have focused on 4 most common cancers, but it is not clear why in each set of cancers they have limited their population. For example for breast cancer, why stage IV was not included? or in lung cancer, why small cell lung was not included. If there is concern about heterogeneity in management, similar heterogeneity can be expected with colorectal cancer stages as well.

2- One of the main limitation of the study is that the data is from a decade ago, and might not be generalizable to current practices.

3- In assigning provider team structure, there has been no mention of mid levels who commonly manage patients as primary care. Why mid levels were excluded from the study?

4- It is not clear why patient sharing with other providers, or count of all providers sharing patients (degree) is increasing among cancer patients vs. controls (in Table 1). Why a single patient cancer diagnosis impacting the patient volume shared?

5- Authors may want to expand on why they think there is differences in adherence based on the chronic condition (why adherence to anti hypertensives higher) or type of cancer. Also there are controversial publications in this area; for example some other papers have shown breast cancer patients will have decreased adherence to chronic medications (as opposed to this study).

6- In supplemental appendix, there is an error displaying Fig 2A-C, and the images could not be visualized.

Reviewer #2: The reviewer has high enthusiasm for this well designed and well written analysis assessing the role of the complexity of the provider team on adherence to chronic disease medications for cancer survivors. This study includes many strengths, including looking at several different cancers and using robust methods with several novel provider complexity metrics. It also offers some good news: that our healthcare system can accommodate increasing provider complexity without risking patient adherence outcomes. These comments and questions are offered in the spirit of improving the clarity of the methods and carefulness of the language in the discussion.

Methods

� At first I was concerned about the exclusion about insurance, as those experience insurance losses may be most vulnerable to adherence challenges. At the same time, I believe this was a strong analytic choice, as it’s important to show that insurance changes were not the cause of non-adherence, and allows the team to further isolate the role of provider complexity.

� Was there censorship due to death? That is to say, that those with poorly coordinated care might have shorter survival. I think not, given that the limitations suggest that only those surviving two years are excluded. I think this is a point worth extracting out a bit: that it’s possible that provider complexity may have been important to survival overall, but, by design, that was not assessed in this analysis.

� I’m not familiar with the term “demeaning”. Is this similar to group mean centering or grand mean centering?

� It seems that this analysis has time nested in patients nested in providers. Were hierarchical models used? If no hierarchical models were used, how would you account for shared variance due to clustering of patients within providers?

� Some of the cancers include long-term therapies that might also compete with comorbidity management. For example, endocrine therapy for breast cancer may be last up to 5 years, and include both oral and intravenous components. Were those medications also accounted for in some way?

Results

� The mediation model adds value, but I also wonder if there are moderating effects. Given the results in the figures showing differences by tumor site, have you explored whether the interaction of provider complexity with tumor site might lead to differences in adherence?

Discussion

� Some of the language in the discussion extends beyond what the results of this study suggest, especially with the language about the need to focus on patient-level factors. Currently, it reads as if patient self-efficacy is the culprit for adherence challenges, as if the problem is that patients just aren’t motivated enough to be adherent. It comes across as victim-blaming and as if increasing a sense of personal responsibility will fix adherence issues. Current interventions for medication adherence for cancer survivors that focus on patient-level factors suggest otherwise1-5. If we can reasonably assume that patients do care about their health to some degree, there are likely competing priorities that may be wholly outside of health care that patients are busy addressing and influences their adherence. While this paper providers strong evidence about complexity of the provider team, there may be other provider-level factors that are still important that are not explored here. It is premature to suggest we should switch to focusing on patient factors. I recommend this language on p14 be revised substantially.

� One of the values of this paper is that it gives us a start on the evidence around the influence of providers: but also leaves more room to explore. For example, might provider complexity influence disparities in adherence? Might there be rural-urban differences to consider or issues of geography? Rather than saying we should immediately shift to patient-level factors, it would be worthwhile to point to other provider-level issues to explore.

References

1. Neven P, Markopoulos C, Tanner M, et al. The impact of educational materials on compliance and persistence rates with adjuvant aromatase inhibitor treatment: First-year results from the Compliance of ARomatase Inhibitors AssessmenT In Daily practice through Educational approach (CARIATIDE) study. The Breast. 2014;23(4):393-399.

2. Ziller V, Kyvernitakis I, Knöll D, Storch A, Hars O, Hadji P. Influence of a patient information program on adherence and persistence with an aromatase inhibitor in breast cancer treatment-the COMPAS study. BMC cancer. 2013;13(1):407.

3. Hadji P, Blettner M, Harbeck N, et al. The Patient's Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer. Annals of oncology. 2013;24(6):1505-1512.

4. Lambert LK, Balneaves LG, Howard AF, Gotay CC. Patient-reported factors associated with adherence to adjuvant endocrine therapy after breast cancer: an integrative review. Breast cancer research and treatment. 2018;167(3):615-633.

5. Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. The oncologist. 2016;21(3):354-376.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Providers’ mediating role for medication adherence among cancer survivors

PONE-D-21-09579R1

Dear Dr. Trogdon,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ilana Graetz

Academic Editor

PLOS ONE