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Navigating Through the Serious Implications of an FDA Warning Letter

Your company has received a Warning Letter addressing certain manufacturing activities that were cited in a 483 form and are now highlighted in the Warning Letter. The FDA routinely issues guidances and other instructions, formal and informal, to assist companies in maintaining good practices with respect to maintenance of their facilities. Still, the majority of companies have received and are all too familiar with what is known in the industry as a Warning Letter. This article addresses examples of underlying conduct while focusing on the following: 1) specific examples in the manufacturing area that could potentially be the subject of the Warning Letter; 2) the guidances and regulations applicable to the cited conduct; 3) steps a company should take to address and respond once it has received a letter; and 4) the potential litigation implications.

Introduction

After an inspection, FDA investigators issue a form FDA-483 which lists the adverse observations made during an inspection. Following the review of the 483 and the establishment inspection report (EIR), the FDA District Office may elect to send the inspected company a Warning Letter.

A Warning Letter differs from an FDA483 in that the Warning Letter indicates that higher level FDA officials, as opposed to an individual investigator or District Office, have reviewed the inspection findings and concluded that the findings warrant formal notification of serious violations.

The Warning Letter is not a final action. The FDA Reference Guide provides: “A Warning Letter is informal and advisory. It communicates the agency’s position on a matter, but it does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action on which it can be sued.”1 Warning Letters, unlike FDA-483s, are posted publicly to the agency’s website (www.fda.gov/foi/warning.htm). Additionally, responses submitted on behalf of the company as to corrective actions are also posted on the same site.

The Federal Food, Drug, and Cosmetic Act, Code of Federal Regulations; guidances from the FDA; and a limited body of case law govern the FDA’s authority to issue Warning Letters and other communications related to manufacturing processes, the effect of such letters on a company’s continued research and development, as well as any potential legal implications.

The Compliance Program Guidance Manual Program provides an outline to the FDA staff on how to handle various aspects of the governing activities, including drug manufacturing inspections.2

Suggested Action for Company

Once a company has received the Warning Letter, certain steps should be followed to assess the background and circumstances of the conduct underlying the Warning Letter. These steps include:

A. Evaluate Violations and the Basis for Violations Cited in Letter.

The company should start by analyzing what the basis was for the Warning Letter and determine whether the inspection giving rise to the Warning Letter was a routine inspection, the result of MedWatch reports, or the result of other specific complaints. The company should assess the status of the inspection and look back at the FDA-483 to analyze observations noted in the FDA483. The company will most likely have already prepared a response to the 483, initially in an exit interview, followed by a formal written response. Additionally, the company should look back to the EIR and analyze inspection observations and links to evidence supporting observations.

B. Preparing the Response and Other Actions to Consider.

A formal response to the Warning Letter will need to be submitted to the FDA.3 Below is a sample outline for what should be included in the response.

1. Statement of commitment to comply with applicable laws and regulations.

2. Statement recognizing the seriousness of the Warning Letter and the company’s commitment to addressing all issues raised.

3. An address of each item in the Warning Letter individually.

4. Scope of corrective action plan, including detailed reports on what has been done and what will be done in the future to correct the issues identified in the letter.

Corrective actions and follow up correspondence updating the agency on each step taken to address the cited conduct should be taken until the company receives a final letter from the FDA stating that “the matter is satisfactorily closed.” In addition to the specific corrective actions put in place to address the conduct cited in the Warning Letter, consider implementing one or more of the following: (1) Policy letter or other formal change to policies to prevent similar conduct in the future; (2) meeting or teleconference with FDA to discuss conduct; (3) depending on the impact that the cited conduct has on a product, consider issuing a recall notice and/or sending a Dear Healthcare Provider Letter informing the field of the cited conduct.

Potential Liability Implications

The Warning Letter could potentially impact litigation involving the manufacturing facility and its products directly. As mentioned above, the Warning Letter and the relevant responses will be publicly available and easily obtained from the agency’s website. While the Warning Letter is not an individual basis for liability, the company should expect to see it in any product liability suit, particularly in the depositions of company representatives. Arguments can be made to exclude the Warning Letter at trial, and in many instances, the company may be successful in excluding the Warning Letter depending on the jurisdiction and extent of connection between the cited conduct and the event giving rise to litigation. However, even if the cited conduct is not directly relevant to the basis for lawsuits, plaintiffs may attempt to use the Warning Letter in any claim against the company to show an alleged pattern or history of bad manufacturing practices.

In assessing liability and the potential impact of the Warning Letter, the company may want to consider taking the following precautionary measures:

1. Collect and maintain all documents pertaining to the cited conduct and the Warning Letter.

2. Collect and maintain Adverse Event Reports that stem from products connected to the facility at issue.

3. Compose a list of individuals with knowledge of the cited conduct and consider conferences between these individuals and the legal department.

Plaintiffs will attempt to use the Warning Letter, as well as any previous Warning Letters or untitled letters, as a basis to show that the company has a pattern or practice of unlawful manufacturing.

The company will have several defenses to the Warning Letter should it be used in depositions and/or admitted at trial. The defenses will be based on the corrective actions taken to address the cited conduct as well as any follow-up actions or correspondence from the FDA. Below are themes that may or may not be applicable depending on the company’s course of action for responding to the Warning Letter and FDA’s decisions.

1. The Warning Letter was not a blanket condemnation of the manufacturing operations at the company. The Warning Letter was a complaint directed at certain discrete events.

2. The company took the FDA’s allegations very seriously and undertook a thorough investigation.

3. To support the argument that the company took the Warning Letter seriously and addressed the cited conduct, the company will rely upon the details of response, including date, content, and any additional follow-up conversations or correspondence.

4. The company took actions to ensure that any product potentially affected by the cited conduct was evaluated, and proper recourse was taken to address any adverse effect.

5. The company corrected the cited conduct by undertaking specific actions to address the processes cited in the Warning Letter.

6. The FDA required no further action and found that the company’s responses were appropriate.

If the company is faced with liability and the Warning Letter is exploited, the company will have arguments to exclude the Warning Letter from being used in litigation. The following analysis is based on the Federal Rules of Evidence and will need to be modified depending on the applicable law.

As part of its regulatory procedures, FDA employees issue untitled letters and Warning Letters to companies to afford those companies an opportunity to correct perceived violations before the FDA decides whether to file an official enforcement action against the company.4 The FDA itself makes clear that a “Warning Letter is informal and advisory” and does not constitute final agency action.5 Warning Letters and other informal FDA letters, therefore, do not meet any of the requirements for a hearsay document to be admissible under the public records or business records exception to the hearsay rule. Such communications provide a preliminary evaluation by FDA staff of a company’s manufacturing practices. They do not report on the activities of the FDA itself.6 The FDA specifically states that it has no duty to issue Warning Letters or other such communications, and therefore the letters are not written “pursuant to duty imposed by law as to which matters there was a duty to report.”7 The Warning Letters and other such communications are communications from FDA staff that precede any official enforcement action and contain allegations not based upon any formal or adjudicated finding of regulatory violations, which constitute opinions rather than factual statistics.8

Finally, the FDA untitled and Warning Letters and other such communications are not the kind of trustworthy report described in Rule 803. Communications such as these lack the trustworthiness required to fall within the hearsay exception because they do not represent the official or final position of the agency.9 Because of this inherent lack of trustworthiness, such communications are also not “business records” under Rule 803(c)(6). Rule 803(6) excepts written records made in the regular course of business “unless the sources of information or the method, purpose or circumstances of preparation indicate that it is not trustworthy.”10

Additionally, the company can argue that FDA Warning Letters or other unofficial statements by FDA employees or participants in FDA advisory committee meetings should be excluded under Rules of Evidence 401 and 403. In the first instance, unless a product at issue was manufactured at the site that formed the basis of the Warning Letter, that letter is simply irrelevant to any of the disputed facts in the case. Moreover, any minimal probative value of this evidence is substantially outweighed by the undue prejudice to the company, confusion of the issues, and undue delay that would result from its admission.

Introduction of informal FDA letters may inaccurately suggest to the jury that the FDA found the company acted improperly, when in fact the letters are not the final and official position of the FDA. The jury may not understand the important difference between the position of an employee of the FDA and a final and official determination of the FDA, attaching undue significance to the contents of any such letter simply because it comes from a government agency.

Admission of these letters and other unofficial statements that appear to be associated with the FDA would also inevitably result in undue delay and needless presentation of cumulative evidence. The company would have to present the jury with evidence that establishes the proper context for any unofficial statements by FDA employees or advisory committee participants and explain why they are not the official FDA position and not binding upon the FDA or the company. This would require evidence of the structure, policies, and procedures of the FDA and its regulatory process and/or evidence regarding the advisory committee structure and process. The company would also be entitled to present evidence and argument to impeach the FDA employee-witnesses or committee participant — something difficult to do if these hearsay statements are admitted and there is no witness to cross examine as to their motives and reasoning in making the statement.

Conclusion

In order to address a Warning Letter received or anticipated, a company should take immediate steps to ascertain the entire basis for the letter and any effects the cited conduct may have on products in the market. In formulating a response, the company should obtain all relevant information and brainstorm a plan of action to address each of the cited items forming the basis for the Warning Letter. The company should consider implementing broader policy changes depending on the likelihood for future problems relating to its manufacturing facilities. In preparation for any potential litigation, the company should be aware that the Warning Letter and its responses will be available in the public domain.


[i] See “Chapter 4: Advisory Actions,” Regulatory Procedures Manual, Section 4-1-1 (March 2004), available at <http://www.fda.gov/ora/compliance_ref/rpm/pdf/ch4.pdf>.

[ii] FDA Compliance Program Guidance Manual Program, Drug Manufacturing Inspections, 7356.002, available at <http://www.fda.gov/ora/cpgm/defaulthtm#drugs>. The CPGMP introduction provides: “FDA compliance programs provide guidance and instructions to FDA staff for obtaining information to help fulfill agency plans in the specified program area. These compliance programs neither create or confer any rights for, or on, any person and do not operate to bind FDA or the public. Alternative approaches may be used as long as said approaches satisfy the requirements of applicable statutes and regulations. These programs are intended for FDA personnel but are made available electronically to the public as they become available.”

[iii] See Chesney, David L. and Anne E. Kelly, “Responding to 483s and Warning Letters,” International Society for Pharmaceutical Engineering, December 1998, available at the ISPE website, <http://www.ispe.org/cs/chapter_web_sites/boston_area_chapter/technical_articles/responding_to_483s_and_warning_letters>. This article summarizes the FDA’s main concerns in reviewing responses to Warning Letters as the following:
What is the impact on the product?
What are you doing about the specific citation?
What was the root cause failure in the implicated quality system and how is that being addressed?
How will you prevent reoccurrence? […]
How and why did this happen?
What could have prevented it?
Who was responsible?

[iv] See “Chapter 10: Prior Notice,” Regulatory Procedures Manual, Section 10-1-3 (March 2007), available at <http://www.fda.gov/ora/compliance_ref/rpm/pdf/ch10.pdf>.

[v] See Chapter 4, supra, Section 4-1-1.; see Summit Tech., Inc. v. High-Line Med. Instruments, Co., 933 F. Supp. 918, 934 n.9 (C.D. Cal. 1996) (“FDA regulatory warning letters do not constitute final agency action” and therefore do not reflect a final conclusion of wrong-doing); Professionals and Patients for Customized Care v. Shalala, 847 F. Supp. 1359 (S.D. Tex. 1994) (“warning letters issued by the FDA are deemed to be informal communications that do not constitute final action”).

[vi] See Lilly, Graham C., An Introduction to the Law of Evidence, §7.19, at 312 (3d ed. 1996) (exception applicable to records of “the internal function of a particular agency” and not “observations of […] conditions external to the office”).

[vii] See Chapter 4, supra, Section 4-1-1 (“FDA is under no legal obligation to warn individuals or firms that they or their products are in violation of the law before taking enforcement action”).

[viii] Accord Smith v. Isuzu Motors Ltd., 137 F.3d 859, 862 (“Our conclusion [to exclude staff memos relating to automobile safety standards because they were not the “factual findings” of NHTSA] is in accord with other circuits that have held that interim agency reports or preliminary memoranda do not satisfy Rule 803(8)(C)’s requirements.”); see also City of New York v. Pullman, Inc., 662 F.2d 910, 915 (2d Cir. 1981) (holding that an interim recommendation by a transit authority staff member to the transit authority administrator was not a factual finding of an agency within the meaning of Rule 803(8)(C) because “the broad language did not embody the findings of an agency, but the tentative results of an incomplete staff investigation”); United States v. Gray, 852 F.2d 136, 139 (4th Cir. 1988) (holding inadmissible “a tentative internal report not purporting to contain agency factual findings”).

[ix] See Toole v. McClintock, 999 F.2d 1430, 1434-35 (11th Cir. 1993) (holding trial court abused its discretion in admitting FDA report regarding safety of breast implants because “Rule 803 makes no exception for tentative or interim reports subject to revision and review”).

[x] Fed. R. Evid. 803(6)

Finis

Citations

  1. See “Chapter 4: Advisory Actions,” Regulatory Procedures Manual, Section 4-1-1 (March 2004), available at <http://www.fda.gov/ora/compliance_ref/rpm/pdf/ch4.pdf>. Jump back to footnote 1 in the text
  2. FDA Compliance Program Guidance Manual Program, Drug Manufacturing Inspections, 7356.002, available at <http://www.fda.gov/ora/cpgm/defaulthtm#drugs>. The CPGMP introduction provides: “FDA compliance programs provide guidance and instructions to FDA staff for obtaining information to help fulfill agency plans in the specified program area. These compliance programs neither create or confer any rights for, or on, any person and do not operate to bind FDA or the public. Alternative approaches may be used as long as said approaches satisfy the requirements of applicable statutes and regulations. These programs are intended for FDA personnel but are made available electronically to the public as they become available.” Jump back to footnote 2 in the text
  3. See Chesney, David L. and Anne E. Kelly, “Responding to 483s and Warning Letters,” International Society for Pharmaceutical Engineering, December 1998, available at the ISPE website, <http://www.ispe.org/cs/chapter_web_sites/boston_area_chapter/technical_articles/responding_to_483s_and_warning_letters>. This article summarizes the FDA’s main concerns in reviewing responses to Warning Letters as the following:
    What is the impact on the product?
    What are you doing about the specific citation?
    What was the root cause failure in the implicated quality system and how is that being addressed?
    How will you prevent reoccurrence? […]
    How and why did this happen?
    What could have prevented it?
    Who was responsible??
    Jump back to footnote 3 in the text
  4. See “Chapter 10: Prior Notice,” Regulatory Procedures Manual, Section 10-1-3 (March 2007), available at <http://www.fda.gov/ora/compliance_ref/rpm/pdf/ch10.pdf>. Jump back to footnote 4 in the text
  5. See Chapter 4, supra, Section 4-1-1.; see Summit Tech., Inc. v. High-Line Med. Instruments, Co., 933 F. Supp. 918, 934 n.9 (C.D. Cal. 1996) (“FDA regulatory warning letters do not constitute final agency action” and therefore do not reflect a final conclusion of wrong-doing); Professionals and Patients for Customized Care v. Shalala, 847 F. Supp. 1359 (S.D. Tex. 1994) (“warning letters issued by the FDA are deemed to be informal communications that do not constitute final action”). Jump back to footnote 5 in the text
  6. See Lilly, Graham C., An Introduction to the Law of Evidence, §7.19, at 312 (3d ed. 1996) (exception applicable to records of “the internal function of a particular agency” and not “observations of […] conditions external to the office”). Jump back to footnote 6 in the text
  7. See Chapter 4, supra, Section 4-1-1 (“FDA is under no legal obligation to warn individuals or firms that they or their products are in violation of the law before taking enforcement action”). Jump back to footnote 7 in the text
  8. Accord Smith v. Isuzu Motors Ltd., 137 F.3d 859, 862 (“Our conclusion [to exclude staff memos relating to automobile safety standards because they were not the “factual findings” of NHTSA] is in accord with other circuits that have held that interim agency reports or preliminary memoranda do not satisfy Rule 803(8)(C)’s requirements.”); see also City of New York v. Pullman, Inc., 662 F.2d 910, 915 (2d Cir. 1981) (holding that an interim recommendation by a transit authority staff member to the transit authority administrator was not a factual finding of an agency within the meaning of Rule 803(8)(C) because “the broad language did not embody the findings of an agency, but the tentative results of an incomplete staff investigation”); United States v. Gray, 852 F.2d 136, 139 (4th Cir. 1988) (holding inadmissible “a tentative internal report not purporting to contain agency factual findings”). Jump back to footnote 8 in the text
  9. See Toole v. McClintock, 999 F.2d 1430, 1434-35 (11th Cir. 1993) (holding trial court abused its discretion in admitting FDA report regarding safety of breast implants because “Rule 803 makes no exception for tentative or interim reports subject to revision and review”). Jump back to footnote 9 in the text
  10. Fed. R. Evid. 803(6) Jump back to footnote 10 in the text