MS: 9003969897730660
Changes in FDA Enforcement Activities Following Changes in Federal Administration: The Case of
Regulatory Letters Released to Pharmaceutical Companies.
We appreciate the comments and suggestions provided by the reviewers. Please find below a point by point response to the reviewers’ comments and suggestions.
Response to Professor Morrato’s review
Main Comments
Other Enforcement Action
The previous reviewer noted that “regulatory letters are only one part of FDA’s enforcement approach. It is important to consider the number and type of FDA enforcement actions filed in federal courts…”. I respect the authors’ response and their statement that this was beyond the scope of their analysis.
However, it should be acknowledged in the limitations section of the discussion.
Notably, there have been several landmark settlements brought by the Department of Justice largely in response to off-label promotion and illegal marketing of drugs. To name a few,
January 2009: Eli Lilly, $1.4 billion
September 2009: Pfizer, $2.3 billion
August 2010: AstraZeneca, $500 million
September 2010: Novartis, $422 million
September 2010: Allergan, $600 million
July 2012: GlaxoSmithKline, $3 billion
Although these cases settled during the Obama administration, I would suspect that allegations and related investigations originated in the previous administration. Therefore, it is important to note that regulatory letters represent just one component of executive administration activity. While I agree that an analyses of these trends were beyond the scope of the present analysis, there would be value in examining trends in Department of Justice action against pharmaceutical companies in future research.
Response: We agree with professor Morrato that regulatory letters represent just one component of executive administration activity and other federal and state departments collaborate in the enforcement of pharmaceutical regulations. While those enforcement activities are outside of the scope of the study, we included the following paragraph in the limitation section of the study:
This study assessed FDA’s enforcement activities. Other federal and state departments also collaborate in the enforcement of pharmaceutical regulations. While those enforcement activities were outside of the scope of this study, future research could examine trends in other components of the executive enforcement.
Moreover, pharmaceutical companies’ activities such as off-label promotion, illegal marketing of drugs or failing to report safety data may result in civil and criminal liability. Cases brought by the federal government against pharmaceutical companies because of illegal behavior have resulted in settlements amounting billions of dollars (Outterson K. Punishing Health Care Fraud — Is the GSK Settlement Sufficient? N Engl J Med 2012;
367:1082-1085.)
Also, I believe Table A is informative and should be referenced as supplemental material. I think the reader will be able to interpret differences between calendar and fiscal years.

Response: We agree with professor Morrato that Table A is informative and the reader will be able to interpret differences between calendar and fiscal years. However, Table A includes pharmaceuticals and other products not assessed in this study and thus, we believe including Table A could be confusing for the reader.
I found it interesting that the number of inspections increased during the Bush administration. I think this might be suggestive of different prioritization of regulatory activities between administrations.
Response: We also think that assessing changes in the number of inspections is an important area for future research.
Limitations for Conclusion
A reviewer in the first round noted that “the conclusion that each administration shapes enforcement policy differently is not surprising given that FDA is an executive branch agency”. I agree with this statement and would like to see this concept incorporated into the Discussion. I think what is noteworthy from the authors’ data on
FDA regulatory letters is how swiftly changes in policy can occur following a change in administration.
Response: We agree with the idea that changes in the administration could lead to changes in enforcement of policies. Nevertheless, it is also worth mentioning that the FDA is one of the most regulated public organizations in the US, employs a substantial number of high level specialist and produces detailed guidelines that should result in more stable policies that those from other public sector agencies. We included the following statement in the discussion section of the study:
Variability in the number of regulatory letters can be related to the behavior of the pharmaceutical companies, changes in drug regulation and policy and changes in FDA’s enforcement procedures implemented during different years of the same administration and also among federal administrations.
Alternative Explanations
The previous reviewer noted that the authors assert that HHS 2002 policy change in regulatory letter review let to the decrease during the Bush administration. For fair balance, the FDA Amendments Act of 2007 should also be referenced as a possible source for increasing regulatory letters during the Obama administration. The primary goal of FDAAA was to strengthen medical product safety. FDAAA enhanced FDA's authority to require labeling changes and additional postmarket studies and to oversee advertising for all drugs. Pharmaceutical companies that were not responsive to requested labeling changes would be in violation of the law and subject to fines. Moreover, FDA can require a company to submit a proposed direct-to-consumer TV commercial for review if the agency has concerns about the content. FDA can also require television and radio drug ads to carry a
"major statement" of an agent's side effects and contraindications. Manufacturers who air false or misleading advertising can be penalized. FDAAA was enacted in the Fall of 2007 during the Bush administration. Thus, this act may be impacting the number of regulatory letters observed in 2008 and beyond as it became implemented, largely during the Obama administration.
Response: We agree with professor Morrato that significant regulatory changes could impact the number and characteristics of warning letters released by the FDA during the period of analysis. We included the following statement in the discussion section of the study:
Regulatory changes may also affect the number and type of regulatory letters. Two significant amendments to the Food, Drug, and Cosmetic (FD&C) Act were introduced during the period of analysis: The Food and Drug
Administration Modernization Act of 1997 (FDAMA) and the Food and Drug Administration Amendments Act
(FDAAA) of 2007. These amendments introduced important changes in the FDA regulation related with postmarketing surveillance and pharmaceutical marketing that could impact the number of warning letters released.

Response to Professor Sansgiry’s review
1) Major Compulsory Revisions
Background: is too lengthy. Needs to be concise. Following sentence can be deleted: 1st paragraph of the background, last sentence: “Investigators from the FDA’s…….. when problems are observed”. This sentence talks about form FDA-483, which is only mentioned in the limitation section.
Response: Following the reviewer comment, we deleted the following sentence:
Inspection is often the precursor to FDA’s enforcement actions. Investigators from the FDA’s district offices conduct nearly all inspections of companies under FDA regulation and issue an inspectional observations form (also called Form FDA-483) detailing the violations when problems are observed [1].
Paragraph 2 and 3 can be combined and written concisely.
Response: We re-worded and combined paragraphs 2 and 3
In cases where no corrective action is taken, prior notice provides evidence that the responsible pharmaceutical company disregarded FDA’s warnings and continued to violate the law [3].
Paragraph 6, last sentence: The sentence could be misleading. The new policy can lead to reduction in number of regulatory letters issued across both types (warning and untitled letters) rather than reduction in “type of letters issued”. The type still remains two (warning and untitled letters).
Response: We thank Professor Sansgiry’s for the clarification. We had rewording the sentence to reflect the fact that policy changes can lead to a reduction in both types of letters (warning letters and notices of violation)
Last paragraph: Authors needs to write more about what they mean by “thorough evaluation”. Seeing the manuscript, it appears that the evaluation although comprehensive (in terms of offices and types of letters); is more of an exploratory attempt. Either elaborate on understanding of “thorough evaluation” or indicate that it was exploratory in nature.
Response: We appreciate the comment and would like to add that this is the first study to assess trends in the pharmaceutical-related warning letters and notices of violation and to assess differences in the average number and type of regulatory letters released during the last four federal administrations.
The paragraph now reads: “no studies have conducted a comprehensive evaluation of the number and type of regulatory letters issued by the different offices of the FDA over a comprehensive period of time covering several federal administrations.”
Objective 1 could be misleading and incomplete; “to assess trends in what? i.e. number of regulatory letters, number or violations in each letter etc. Please refine the objective. Essentially, objective 1 and 2 mean the same.
The second object would rather focus on “variability in number of regulatory letters by type and releasing offices”.
Response: Thank you for the suggestion. We have revised the objectives as follows:
The objectives of this study were two-fold: 1) to assess trends in the number of pharmaceutical- related warning letters and notices of violation released by the FDA between 1997 and 2011; and 2) to evaluate differences in the type of regulatory letters released during the last four federal administrations by type of regulatory letter and releasing office.

Discussion last paragraph: The last two sentences of the discussion are a great leap form what the results indicate. The results of this study merely indicate that there was variability (reduction) in issuance of regulatory letters. But attributing this reduction to scare resources and eventually indicating that safety of pharmaceuticals is compromised is not appropriate. It is important to mention that there could have been increase in other surveillance measures.
Response: We appreciate Professor Sansgiry’s comment. We acknowledged that “ the reduction in the number of regulatory letters, especially notices of violation, may derive from the prioritization of FDA’s limited resources.
” We also stated that “ A further assessment of the impact of changes in federal administration on the enforcement policy of the FDA is required”.
- Minor Essential Revisions
Abstract:
Background: For better understanding, the sentence “These enforcement activities….” Can be re arranged as
“These enforcement activities include regulatory letters (warning letters and notice of violation/untitled letters) sent to pharmaceutical companies accounting for product/activity violations”. Delete the following sentence.
Response: Background section reads: “These enforcement activities include regulatory letters (i.e. warning letters and notice of violation) to pharmaceutical companies.”
Results: “During the 2nd Clinton Administration (1997-2000) the average number of regulatory letters…..” add the highlighted word.
Response: Results section reads: “During the 2nd Clinton Administration (1997-2000) the average number of regulatory letters per year was 242.8±45.6”
Authors need to be consistent in using of terminology across the manuscript specifically, “regulatory letters” Vs.
“warning letters” Vs. “notices of violations”.
Response: A thorough examination of the use of terms “regulatory letters”, “warning letters” and “notices of violations” was conducted. Changes have been highlighted for your convenience.