Analyzing Black Market Sales of the Second-Line ADHD Medication Atomoxetine

Round 1

Reviewer 1 Report

Dear Author(s),

Thank you for your interesting and relevant manuscript regarding black market diversions of atomoxetine.

Topic is important, introduction is informative enough, aim is clear, and results and discussion follow. Conclusions are correct.

I only have minor comments all related to methodology paragraph which should be improved definitely.

-Include the info on StreetRx coverage

-Please provide more extensive description od StreetRx alongside with its pros and cons from the data collection and pharmacoepidemiology perspective

-More strengths and limitations should be stated within the discussion paragraph 

Best regards, Reviewer

Author Response

Thank you for your interesting and relevant manuscript regarding black market diversions of atomoxetine. 

Topic is important, introduction is informative enough, aim is clear, and results and discussion follow. Conclusions are correct. 

Thank you for this feedback 

I only have minor comments all related to methodology paragraph which should be improved definitely. 

-Included the info on StreetRx coverage

– see lines 51-60... is location what you mean by coverage? 

-Please provide more extensive description of StreetRx alongside with its pros and cons from the data collection and pharmacoepidemiology perspective 

Great suggestion. See lines 178-189

-More strengths and limitations should be stated within the discussion paragraph  

Strengths and Limitations is now a separate section, see 171-189

Reviewer 2 Report

In this study, the authors analyze black market diversions of atomoxetine from 2015 to 2019. The overall topic and the used database are very interesting; however, the study would benefit from a clearer (clinical/pharmacoepidemiological) study question and respective analyses.

Introduction:

·       Although including important points, the introduction would benefit from a clearer structure as several aspects (e.g. second line, unscheduled, low abuse potential) are mentioned repeatedly at different places.

·       Further, the motivation/rationale for this study does not become clear and I would appreciate a more clinical/pharmacoepidemiological (and clearly developed) research question.

Methods:

·       The description of the database should be moved to the methods section. Please also consider a more detailed description of StreetRx.

·       Have other pharmacoepidemiological studies been conducted with this database?

Results/analysis:

·       I recommend a stratified analysis over the years (per year or before/after the approval of generic atomoxetine), presented in a table, to display trends in e.g. products, costs and states.

·       These trends should then be taken up in the discussion.

Discussion:

·       The discussion should include more comparisons to other ADHD drugs/stimulants and their respective trends. Currently it is unclear whether 113 purchases represent a (comparatively) large or a small number.

·       According to the FDA site, the first generic atomoxetine was approved in 2017, this should be addressed (see recommendation for analyses above).

·       The Covid pandemic did not overlap with the study period, therefore the large proportion of the discussion spent on this topic is not clear to me.

Abstract: The conclusion should (at least in parts) reflect/refer to the study results.

Please check for typos (e.g. lines: 77, 104, 146,)

Author Response

In this study, the authors analyze black market diversions of atomoxetine from 2015 to 2019. The overall topic and the used database are very interesting; however, the study would benefit from a clearer (clinical/pharmacoepidemiological) study question and respective analyses. 

Introduction: 

• Although including important points, the introduction would benefit from a clearer structure as several aspects (e.g. second line, unscheduled, low abuse potential) are mentioned repeatedly at different places. addressed, deleted repetitiveness
• Further, the motivation/rationale for this study does not become clear and I would appreciate a more clinical/pharmacoepidemiological (and clearly developed) research question. Added, see lines 6-8 

Methods: 

• The description of the database should be moved to the methods section. Please also consider a more detailed description of StreetRx. Moved, see improved methods starting at 52
• Have other pharmacoepidemiological studies been conducted with this database? Yes, see methods for strengths weaknesses and past studies.  

See methods 

Results/analysis: 

• I recommend a stratified analysis over the years (per year or before/after the approval of generic atomoxetine), presented in a table, to display trends in e.g. products, costs and states. 

Added: Before approval of a generic atomoxetine, the average price per milligram was $1.38 (N=65; SD=$2.86), whereas after approval of a generic form of atomoxetine, the average price per milligram was $1.31 (N=48; SD=$2.68). 

• These trends should then be taken up in the discussion.

Added: This could partially be attributed to a generic form of atomoxetine not taking market until mid-2017, with the average price of black market sales dropping $0.08 per milligram after it did. 

Discussion: 

• The discussion should include more comparisons to other ADHD drugs/stimulants and their respective trends. Currently it is unclear whether 113 purchases represent a (comparatively) large or a small number. 
• According to the FDA site, the first generic atomoxetine was approved in 2017, this should be addressed (see recommendation for analyses above). 

Added: This could partially be attributed to a generic form of atomoxetine not taking market until mid-2017, with the average price of black market sales dropping $0.08 per milligram after it did. 

• The Covid pandemic did not overlap with the study period, therefore the large proportion of the discussion spent on this topic is not clear to me. 

Abstract: The conclusion should (at least in parts) reflect/refer to the study results. 

Added: The per milligram cost of atomoxetine on the black market is over 50 times the per milligram cost of the generic prescribed form. 

Please check for typos (e.g. lines: 77, 104, 146,) 

Checked

Author Response File: Author Response.docx

Reviewer 3 Report

This is an interesting study on black market sales of atomoxetine, a second-line ADHD drug, using a novel data source. I have several suggestions that may help strengthen the manuscript.

1.      It’d be helpful to include how many submissions there were each year.

2.      In Figure 2, I would have states with no submissions as a separate category so that readers can easily tell where the data points came from.

3.      The distribution of the price per milligram would also be interesting, in addition to the mean and SD, such as the 25^th percentile, median, 75^th.

4.      In the abstract, possible reasons for black market atomoxetine purchase are really not based on the analyses in the paper. I would take them out of the abstract.

Author Response

This is an interesting study on black market sales of atomoxetine, a second-line ADHD drug, using a novel data source. I have several suggestions that may help strengthen the manuscript. 

1. It’d be helpful to include how many submissions there were each year. Thank you for the suggestion, we were unable to add at this time. 
2. In Figure 2, I would have states with no submissions as a separate category so that readers can easily tell where the data points came from. Thank you for the suggestion, we were unable to add at this time.  
3. The distribution of the price per milligram would also be interesting, in addition to the mean and SD, such as the 25^th percentile, median, 75^th. Thank you for the suggestion, we were unable to add at this time. 
4. In the abstract, possible reasons for black market atomoxetine purchase are really not based on the analyses in the paper. I would take them out of the abstract. We deleted see lines 17-17 

Author Response File: Author Response.docx

Reviewer 4 Report

Dear Author

"Analyzing Black Market Sales of the Second Line ADHD Medication, Atomoxetine" is an interesting report.

- In methods "Data included the generic drug name, drug dosage, purchase price, and date and location of submission in the United States from 2015 to 2019 for atomoxetine". 

Why didn't you mention about the drug dosage in your results?

Was there any missing information? If so, how did you compromise it?

When did you conduct the study?

Why did you collect data only till 2019? Now we are in 2023 and almost 4 years lag behind.

- Provide Institutional Review Board approval number.

- In results, figure 1 is unnecessary, since it provide the same information as written in the text.

- Your discussion talks more about adverse effects of the drug, which was not the objective of your study. Focus on your study results in the discussion part.

Kindly edit the whole manuscript for typographical errors. For instance:

- Line 77 - Moreober

- Line 104 - withdrawl

- Line 142 - als

-Line 146- prscribe

Author Response

"Analyzing Black Market Sales of the Second Line ADHD Medication, Atomoxetine" is an interesting report.

- In methods "Data included the generic drug name, drug dosage, purchase price, and date and location of submission in the United States from 2015 to 2019 for atomoxetine".

we inserted this, see line 58-59

Why didn't you mention about the drug dosage in your results?

Thank you for this question. We added this; see line 76-78.

Was there any missing information? If so, how did you compromise it?

Thank you for this question. entries with missing information were deleted.   

When did you conduct the study?

2021

Why did you collect data only till 2019? Now we are in 2023 and almost 4 years lag behind.

Thank you for this question. Unfortunately there has been no new data available 

- Provide Institutional Review Board approval number. 

2022-0213. Is now in the text  

- In results, figure 1 is unnecessary, since it provide the same information as written in the text.

Ok, we deleted this.   

Your discussion talks more about adverse effects of the drug, which was not the objective of your study. Focus on your study results in the discussion part.

Thank you for this question. We did discuss our study results in lines 86-97. We feel that the additional discussion of atomoxetine's mechanism, genetic factors, off-label uses, safety of use, etc. augments the paper because it gets at the real-world implications of the reported black market diversion.  

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors improved the manuscript. However, there still is the issue of the (clinical/pharmacoepidemiological) study question/objective. The objective's wording in the abstract is improved but this should be also placed in the end of the introduction (instead of in the methods). Further, the lead to the study question which is usually developed by describing a research gap which can/will be addressed by the study should still be improved.

Author Response

Thank you for this feedback. Please see how we expanded upon the research question (lines 25-25) and introduction (55-59). Thank you and please reach out with any additional questions or recommended changes.

Author Response File: Author Response.docx