FDA Warning Letter System and Its Enlightenment to China

ZHAO Pin, YANG Yue



FDA Warning Letter System and Its Enlightenment to China

ZHAO Pin, YANG Yue

Objective To provide a reference for the establishment of a warning letter system and the improvement of current warning practices in China based on the analysis of content and layout of FDA warning letters. Methods Experience summarization methods were adopted to analyze the warning letters issued by FDA from January to December in 2013. Results and Conclusion US FDA has developed a standardized model of the warning letters based on certain theory and evaluation methods after a long-term practice, which has some enlightenment to China.

warning letter; violation; information disclosure

The formulation and promulgation of drug warning information have been the weak link in China’s drug inspection. In recent years, with the increasing drug inspection in the world, China Food and Drug Administration (CFDA) learned from the US Food and Drug Administration (FDA) to take a range of regulatory measures including a warning letter to those who do not comply with Chinese laws and regulations. For domestic enterprises, CFDA’s warning letter system has not been established.

1 Definition

FDA began to publish the warning letter content on its official website to make it open to the public after the Electronic Freedom of Information Act Amendments was promulgated in 1996. In 2009, FDA launched Transparency Initiative to monitor and assess executive status of regulatory measures and notify the results to the public with Close-Out. That contributed to two-way communication between regulatory objects and health authority.

FDA defined the warning letter as “a letter which is used to inform the regulatory objects that they have illegal facts documented in FDA’s inspection or investigation[1], that is, enterprises and individuals who violate the Federal Food Drug and Cosmetic Act, Regulations and other federal regulations, FDA would inform them with a warning letter before enforcing an action, and allows them to take voluntary, timely and effective corrective action. FDA does not have the duty to inform violations to illegal enterprises or individuals. A warning letter is based on a prospective basis that enterprises and individuals will abide by the law.

2 Procedures

662 warning letters were issued by FDA in 2013, and 108 involved pharmaceutical enterprises and individuals[2](See Table 1).

Table 1 Warning letters issued in 2013

TypeN(%)ObjectsRegulations cGMP violation36/33.3Pharmaceutical enterprisesFD&C Act section501(a)(2)(B) Labeling error9/8.3Pharmaceutical enterprises, enterprises for food, dietary supplementFD&C Act section301(a);502(a);502(f)(1);503(b)(4) Unapproved drug48/44.4Pharmaceutical enterprises, enterprises for food, dietary supplementFD&C Act section505(a) Clinical trial violation13/12.0Clinical investigator, investigational review board, contract research organization21CFR312.305;312.50;312.53;312.56;312.60;312.62;312.305 Other2/1.9Pharmaceutical enterprisesGDUFA; FD&C Act section 510(i)(1)

Note: CGMP means Current Good Manufacture Practices; FD&C Act means Federal Food, Drug, and Cosmetic Act; CFR means Code of Federal Regulations; GDUFA means Generic Drug User Fee Amendments.

Before issuing a warning letter, agency should take the following issues into consideration[3]:

(1) Evidence shows that a firm, product, and/or individual is in violation of the law or regulations and fails to take a prompt correction;

(2) The violations are serious and the enterprises will face FDA law action without correction. The warning letter is appropriate and consistent with agency policy;

(3) There is a reasonable expectation that the responsible firm and person will take prompt corrective action.

When a firm is in the process of correcting the violations or has made a written promise to take prompt corrective action, the regulatory should consider the following factors when determining whether or not to issue a warning letter:

(1) The firm’s compliance history, e.g., a record of serious violations, or failure to prevent the recurrence of violations;

(2) The nature of the violation, e.g., a violation that the firm is aware of but failed to correct;

(3) The risk associated with the product and the impact of the violations on such risk;

(4) The overall adequacy of the firm’s corrective action and whether the corrective action addresses the specific violations, related violations, related products or facilities, and it contains provisions for monitoring and review to ensure effectiveness and prevent recurrence;

(5) Whether documentation of the corrective action is provided to enable the agency to undertake an informed evaluation;

(6) Whether the timetable for the corrective action is appropriate and whether actual progress has been made in accordance with the timetable;

(7) Whether the corrective action taken ensures sustained compliance with the law or regulations.

If the regulatory thinks that an adequate corrective action has been taken and related violations have been corrected, a response letter would be issued instead of a warning letter. A response letter indicates that the agency is relying on the firm’s corrections or commitment regarding corrective actions. Furthermore, the letter includes a statement that sustained attention will be paid to these or similar violations. Regulatory actions (e.g., seizure, injunction and civil penalties) may be taken without further notice.

The warning letter for labeling errors, computer application and software violations, bioresearch monitoring program violations and product advertising violations will be issued by all centers, the other warning letters will be issued by FDA and district offices respectively. The Compliance Management System (CMS) is now being used for electronic submission of warning letter recommendations from district offices. All recommendations by the district offices must use CMS for submitting the proposed warning letter (see Figure 1).

The Center for Drug Evaluation and Research (CDER) is responsible for issuing warning letters involving drugs, including:

(1) New drug charges;

(2) Adverse drug experience reporting violations;

(3) Novel and unusual tamper-evident packaging violations;

(4) Prescription Drug Marketing Act violations;

(5) Investigational drug use violations;

(6) CGMP charges involving active pharmaceutical ingredients and other drug component manufacturing deficiencies;

(7) CGMP charges involving all dosage forms, including medical gases;

(8) CGMP charges involving inspections of facilities for therapeutic biologic product;

(9) Pharmacy compounding issues;

(10) Violations related to required post-marketing studies and clinical trials.

Figure 1 Process of information disclosure

FDA issues warning letters on website. An official close-out letter will be issued based on confirmation by FDA that the violations in the warning letter have been adequately addressed by enterprises and individuals. In addition, FDA can decide whether to post the enterprises response to warning letter on website based on requirement of receivers.

3 Content and layout

To fully set forth the nature of violations and achieve the desired warning effect, the content and layout of a warning letter must be accurate, efficient and flexible.

By analyzing the warning letters issued by FDA, we divided the elements into three parts, fixed elements, variable elements and selective elements (see Table 2). Fixed and variable elements are necessary for the contents of the warning letter. The fixed elements are the type of warning letter and irrelevant to companies. Some adjustment should be made for the variable elements to the warning objects. The selective elements can be modified based on the type of warning letters if necessary.

Table 2 Elements of FDA warning letter

TypePartContent Fixed elementsTitle“Warning letter” Disclaimer“The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist [at your facility/in connection with your product(s)]. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that [you/your firm] comply [-ies] with all requirements of federal law and FDA regulations.” Statement“You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.” Instruction“Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction.” Way of response“Please send your reply to the following address:” Selective elementsLaw & regulationInclude citation of the section of the law and, where applicable, the regulation violated. PMRs & dateWarning Letters not based on inspections and citing violations of statutory requirements for studies such as post-marketing requirements (PMRs) and clinical trials should cite the appropriate application number, PMR reference number (if appropriate) and date that the applicant was notified of the PMR. Instructions for responseInstructions, as appropriate, that the response include: a. each step that has been or will be taken to completely correct the current violations and to prevent similar violations;b. the time within which correction will be completed;c. any reason the corrective action has not been completed within the response time; and,d. any documentation necessary to show that correction has been achieved. Statement of cGMP violation“If CGMP violations are cited, a statement regarding the potential impact on requests for approval of export certificates and drug applications.” Description of shortage“If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov in order to ensure that your action(s) does not adversely affect the public health.” Description of suspend“If you no longer manufacture or market a certain product, your response should indicate, including the reasons that, and the date on which, you ceased production. Also, please indicate your progress in updating the drug listing files in accordance with 21 CFR 207.30(a) (2).” Way of download“Note: Contact CDER director, Division of Domestic Drug Quality for a copy of the Microsoft Word version format for the CDER cGMP warning letter.”

Take the warning letter of cGMP violation as an example, it includes:

In terms of the delivery of warning letters, FDA requires the warning letters should have overnight delivery and retain records with receipts. Meanwhile, the warning letter should be addressed to the highest known official in the corporation that includes the facility that was inspected, and a copy should be sent to the highest level of known manager at the inspected enterprise. Therefore, the date, the way, the recipient’s name, title and address should be clearly marked below the title of warning letters.

The first part of the warning letter is the summary which clarifies synoptically the date, manufacturer name and address of inspection by FDA, major violation of enterprise, related regulations and provisions, and defines the violation facts (such as adulterated drugs).

The main part of a warning letter will give a brief description of the violations, and then the specific items and related provisions are made in the form of project number. For enterprises who have responded to the issues raised by FDA inspectors, a warning letter would involve appropriately correction commitment made by companies to the regional office during the examination with 483 forms. But it stated that “We found it lack of adequate corrective measures after we evaluated your company’s response” at the same time.

For all violations, the specific composition of elements include: violation of statutory provisions, example of violation, correction commitment from enterprise, reasons indicating that corrective measures are not sufficient, guidance to correction (such as the relevant guidance). For non-first violation, a warning letter would mention the date of inspection records with emphasis.

As fixed elements of FDA warning letter, the end of the warning letter covers claimer, statement of warning, instructions and way of response.

In terms of drafting the warning letter, FDA warning letters have characteristics as below:

The fixed elements of warning letters for different types of businesses or individuals are identical. This template design ensures the integrity of the contents of the warning letter. At the same time it fully ensures the release of the letters which helps enterprises to take timely corrective measures to safeguard public health and safety.

Words of warning letters used in the sentence and layout have a certain consistency to help readers quickly lock key content to get the information which is more helpful for the readers. In addition, the use of relatively fixed terms to avoid ambiguity for readers to ensure the accuracy of the information conveyed.

Overall, the full text of a warning letter uses the form from the general to the points. That is to itemize violation items in the form of project number after synoptically stating the violations of enterprises or individuals. In addition, for each enterprise or personal violation, relevant statutory provisions are cited to ensure the persuasive information and reinforce the warning effect.

4 Inspirations

In order to strengthen risk management of drug manufacturers, China’s Adverse Drug Reaction Monitoring Center established “the company drug safety warning information” to release safety-related information caused by manufacturers of medical personnel in March 2013. But currently it has not worked yet. And warning letters for overseas inspection enterprises have not yet issued to the public. If we want to make the warning letter to play the role in crisis prevention, the current regulatory measures should be improved to achieve regulatory information open and transparent.

The prominent advantage of warning letter system lies in full trust of enterprises’ abiding consciousness. On this basis, the regulatory can warn enterprises the consequences of their violation. The establishment of the system can strengthen the law-abiding awareness of China’s enterprises and effectively reduce the regulatory agencies and law enforcement costs, while playing the role of risk warning. But so far, China has not yet established a warning letter system for the domestic pharmaceutical enterprises violation.

As to the published warning message (such as adverse reactions communications), there are some problems, such as lack of standard representation and format. Therefore, a warning letter should have fixed elements for different types of violations with fixed content and templates. We should make periodic assessment and adjustment to improve its distribution efficiency and ensure the normative and consistency of information to achieve the desired warning effect.

[1] DUAN Ran. Effect of Warning Letter [J]. Chinese Pharmaceutical Affairs, 2013, 27 (3): 332-337.

[2] FDA. Warning Letter [EB/OL]. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/default.htm, 2014-03-06.

[3] FDA. Warning Letter Procedure [EB/OL]. http://www.fda.gov/iceci/compliancemanuals/regulatoryproceduresmanual/ucm176870.htm, 2012-08-01.

Author’s information: YANG Yue, Professor. Major research area:Pharmaceutical regulations, drug policy. Tel: 13998236315, E-mail:yyue315@126.com