In early July, FDA released a draft guidance entitled, “Field Alert Report Submission – Questions and Answers – Guidance for Industry” (Guidance), which covers the requirements for submission of field alert reports (FARs) by applicants of new drug applications (NDAs) and abbreviated new drug applications (ANDAs), domestic and foreign, and outlines FDA’s recommendations for FAR submissions in an effort to increase consistency and relevancy.

FARs have been a point of confusion for industry since they were first required. The Guidance document reviews some frequently asked questions under six focused subject headings:

1. What is a FAR and what triggers its submission?
2. Who is responsible for submitting the FAR?
3. When should I submit a FAR?
4. How do I submit a FAR?
5. Where do I submit a FAR?
6. Should I submit a follow-up or final FAR?

To summarize, a Field Alert Report, or FAR, is a rapid notification to the FDA of a potential quality or labeling issue with a drug product which may cause a health or safety risk. The FAR is to be submitted by the NDA/ANDA applicant; even if there is a contractual agreement with another person or entity, the NDA/ANDA applicant is ultimately responsible for submission. The FAR is to be submitted within three working days of receipt of the information meeting FAR criteria. The best way to submit the information is via electronic form FDA 3331a. If more than one NDA/ANDA is involved, one form per NDA or ANDA is required. The electronic form FDA 3331a will automatically submit the form to CDER and the FDA district office selected. Follow-up and final FARs are not required, but they are recommended to be filed as soon as possible to assist FDA’s assessment of the risk to public health and the adequacy of the firm’s response.
Let’s take a closer look at the content of the Guidance.

What is a FAR and what triggers its submission?
There are several situations that would require the submission of a FAR by a drug sponsor:

• An incident that causes a drug product or its labeling to be mistaken for, or applied to, another article;
• bacteriological contamination;
• significant chemical, physical, or other change or deterioration in the distributed drug product; and
• failure of one or more distributed batches of the drug product to meet the specification established in the application.

Determination of whether or not a change is significant involves an evaluation of the potential impact on the drug product’s identity, strength, purity, stability and efficacy as well as how this change could impact an individual using the product. Changes could be based on factors specific to the distributed product, such as intended use, route of administration, dosage, etc. Determination of significant changes should be documented in an investigation, with the determined rationale for the final decision to include the factors specific to the distributed product that were considered. Significance can be misinterpreted, depending on the level and location of investigation. This is further complicated by complex contractor/customer relationships.

For example, if a CMO finds that there is a gasket or screw missing from a piece of equipment that might have fallen into a batch, they may investigate it as unrelated to any batch or customer product. However, in certain situations, this might require the need to notify the customers, and necessitate the filing of a field alert. If the customer isn’t notified, and/or a field alert isn’t filed, this could result in 483s at both the CMO—for not notifying the NDA/ANDA applicant per the Quality Agreement—and the customer—for not submitting a FAR or lack of supplier oversight.

Who is responsible for submitting the FAR?
Ultimate responsibility for submitting a FAR lies with an NDA/ANDA applicant. A contractual agreement such as a Quality Agreement with a third party to manufacture, hold, package, label or distribute product does not release the applicant from the ultimate responsibility to file a FAR. There are constant communication needs outlined in Quality Agreements and communication goes both ways. Just as a CMO needs to alert the applicant within a short period of time if there is a potential issue, the applicant also needs to communicate to its CMO if a relevant FAR is issued. Consider the difficulties that could arise if a CMO is not contacted when a FAR is submitted. A field alert, depending on the source or reason, may require changes to processes or procedures that a CMO would need to be aware of. For this reason, a Quality Agreement should include expectations for reporting and communication to respective CMOs in case of unexpected events and related changes that could result in a FAR. The Guidance recommends that a procedure be established, followed and maintained for receiving and responding to reportable information from contracted entities regarding products.

When should I submit a FAR?
FARs are to be submitted to FDA within three working days of when the information is received. Failing to meet the required three-day time frame is a violation of section § 314.81(b)(1) as well as section 505(k) of the Federal Food, Drug, and Cosmetic Act. Failure to report on time may also result in a regulatory action, even if this is not cited on a Form FDA 483 during the next inspection. Not filing on time is incredibly easy for the FDA to detect, and many companies utilize systems that track this information. It is important to keep in mind that delays in reporting from the CMO could lead to delays in reporting from the applicant.

How do I submit a FAR?
The Guidance recommends electronically submitting FARS using Form FDA 3331a. This will expedite the FDA’s review process as well as meet submission obligations to the respective district office. A paper copy of Form FDA 3331a is not necessary if the electronic submission is used; however, if a FAR is initially submitted by telephone, a Form FDA 3331a should also be submitted electronically. The Guidance provides that if all information requested is not available at the time of the initial FAR, a follow-up FAR can be submitted to update information.

FARs that are associated with more than one NDA/ANDA are to be submitted using separate forms initially; one for each application affected. If there is one comprehensive investigation conducted into a facility-wide problem which affected multiple applications, one follow-up, or final FAR referencing all NDA/ANDA number(s) affected can be submitted.

Initial, Follow-up and Final FARs are all not all required, but are recommended by the Guidance. An initial FAR is submitted to meet the requirements of § 314.81(b)(1) and is the first time information is reported regarding a specific problem.

A follow-up FAR is not required, but is recommended as a method to submit significant additional information in regard to the problem identified in the initial FAR. “Significant” additional information may include correction of previous information submitted, expansion of the lots identified, test results now provided, and identification of potential root causes; as examples of information to be submitted with a follow-up FAR. As noted in the Guidance document, a follow-up FAR should not be submitted if all of the following are true:

• The problem is the same as that identified in the initial FAR;
• The drug product is covered under the same NDA/ANDA as originally reported;
• The investigation into the root cause of the initial FAR is still ongoing; and
• The drug product is part of the same lot as originally reported.

A final FAR is used to identify the root cause of the issue, describe any corrective action, and close out the initial FAR.

Where do I submit a FAR?
Field Alert Reports are to be submitted electronically to CDER and the FDA district office responsible for the facility, as selected on the form. If necessary, CDER will forward the FAR to CBER. For foreign facilities, list the address where the problem occurred (foreign) and the FDA district office where the firm’s attorney, U.S. agent or other authorized official resides. If there are multiple firms or locations involved, the name and address of the finished drug product manufacturer for the NDA/ANDA should be listed as the firm where the problem occurred. Similarly, if the product is an API or raw material, the supplier’s facility would be listed. Lastly, if it is unclear where the issue has occurred, it is best to list the site the problem most likely occurred, using the information available. Information submitted can be updated at any time using a follow-up FAR.

Should I submit a follow-up or final FAR?
Follow-up and final FARs are not required. However, if additional information is available, it is recommended to file as soon as possible in order for the FDA to assess the risk to public health and the adequacy of a firm’s response. It is recommended to submit a final FAR promptly following the identification of the root cause, if corrective action is taken, or the investigation is closed.

Conclusion
Although there has been information on the web for years regarding the submission of Field Alert Reports, the newly issued draft Guidance appropriately places all of the priority information in one easy to reach reference location. 


References
Food and Drug Administration, “Field Alert Report Submission – Questions and Answers – Guidance for Industry: Draft Guidance”, July 2018, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM613753.pdf

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Constance Richard-Math
Lachman Consultants

Constance Richard-Math is a Director in the Compliance Practice who joined Lachman Consultants after a 20-year career at the U.S. Food and Drug Administration where she rose to the position of Director, Investigations Branch at the Baltimore, Maryland District Office. While at FDA, she oversaw a large group of operational Consumer Safety Officers, regularly provided technical and programmatic advice to branch employees and reviewed inspectional reports. Ms. Richard-Math is experienced in pharmaceuticals (API, tablet/capsule, injectable, and topical dosage forms), medical devices, human and animal foods, biomedical research, cosmetics, and import operations.