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In February, FDA released a draft guidance entitled “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act.

Section 503B refers primarily to compounding pharmacies and Good Manufacturing Practices (GMP). This draft guidance notes that and then notes that such facilities must submit adverse events (AEs) under 21CFR310.305 which are the well known (to us in the PV world) regulations for post-marketing AE reporting.

This draft guidance then goes on to describe in detail the AE/SAE reporting under 21CFR310. Although intended for compounders, this guidance really is giving information to everyone, not just compounders, who submits SAEs and AEs to FDA for marketed products.

There is a lot of interesting and, arguably, new information in here. Thus a careful review of this document is worth doing as it expresses FDA’s thinking on SAE/AE reporting.

The initial section of the document describes the regulatory background for this guidance and is aimed at outsourcing and compounding facilities. Although not directly stated here, this document has been issued following a tragedy a couple of years ago relating to contaminated, compounded drug products. This section indicates that FDA has the legal authority to regulate these products and require SAE/AE reporting.

Section 310.305

This is a review of definitions: serious adverse drug experience (ADE) and unexpected ADE. You can read these definitions in this draft. There are no surprises here. In regard to the compounders, FDA notes that each ADE received or “otherwise obtained” (not clear what this means) that is both serious and unexpected must be reported as soon as possible, but in no case later than 15 calendar days of initial receipt of the information along with a copy of the drug product’s current labeling. Investigation and follow up should be done for all serious, unexpected ADEs and new information submitted with 15 calendar days of its receipt. Straight from the regulations.

“Information on the names and addresses of individual patients should not be included.” [Bold italics are from FDA]. A unique code number should therefore be assigned instead for each patient and placed in section A1 of the MedWatch (3500A) form.” Firms must “maintain certain records relating to ADEs for 10 years and provide FDA access to them.”

“The regulations also provide a disclaimer that the report or information submitted (and any release by FDA of that report or information) does not necessarily reflect a conclusion that the report or information constitutes an admission that the drug caused or contributed to an adverse effect.”

Comment: Straightforward and no surprises but a clear statement of data privacy in regard to patient identification and data retention.

AE Reporting by Outsourcing Facilities

The next section is specific to compounding facilities and extends the reporting to all serious ADEs, not just serious, unexpected ones:

“In addition, FDA strongly recommends that outsourcing facilities report all serious adverse drug experiences associated with their compounded prescription drug products. We believe reporting all serious adverse events would provide important information about potential product quality issues or public health risks associated with drug products compounded by outsourcing facilities.” Again, the bold italics are in the draft document emphasizing that FDA wants all SAEs for compounded products.

Comment: For compounding pharmacies, this is above and beyond the regulations and FDA is saying the reporting of all SAEs is a “recommendation”. It is highly unlikely that this section should be extrapolated to all other drug products as there is clear sensitivity to compounded products and FDA is putting a lower threshold on reporting of compounded products SAEs. I imagine there will be some comments to FDA to clarify this to be sure it does not pertain to other non-compounded products. Is this a harbinger of the future when all of America is on electronic health records and FDA can pull in all SAEs (and non-serious AEs)?

Threshold for Reporting

Next the FDA describes the four minimum criteria for a valid report (identifiable patient, identifiable reporter, suspect drug, SAE). Of interest, however, is the next section that states (again in bold type): “Reports should be submitted as long as the outsourcing facility has information on at least the suspect drug and the adverse event.”

Comment: This is different from the usual procedures we follow for drug SAEs. We usually do not report until all four minimal criteria are met. As above, not clear that this should be extrapolated to non-compounded drug products. One hopes FDA will clarify in the final regulation.

Identifiable Patient

This is defined here to be enough information “to indicate the existence of a specific patient”:

Further instruction is given: “A report stating that “an elderly woman had anaphylaxis” or “a young man experienced anaphylaxis” would be sufficient. If a report refers to groups of unknown size, such as “some” or “a few” college students had anaphylaxis, the outsourcing facility should follow up to find out 
how many students were involved and submit a separate report to FDA for each student, because each is considered to be an identifiable patient. The outsourcing facility should distinguish each identifiable patient so that it is clear that each report is not a duplicate report of a single adverse event.”

Comment: No surprises here and this is how most people handle these reports. Good to have it clearly spelled out.

Identifiable Reporter

Similar to the above. “A reporter is a person who initially notifies the outsourcing facility about an adverse event. An initial reporter can be a patient, consumer, family member, doctor, pharmacist, other health care professional, or other individual. The outsourcing facility should obtain, if possible, sufficient information to indicate that the reporter is an identifiable person who purports to have knowledge about the patient, adverse event, and drug involved. One or more of the following would qualify a reporter as identifiable:

Comment: Similar to the identifiable patient section. At least here, FDA notes that an email address is acceptable. Presumably it would be acceptable for an identifiable patient also. Nothing specific beyond this on social media which are now playing a bigger and bigger role in everything we do.

Next FDA talks about doing obligatory follow up and then addresses requests for anonymity:

“If an identifiable reporter provides contact information, but requests that the outsourcing facility not forward this information to FDA, the outsourcing facility can submit a report to FDA without specifically identifying the reporter by filling out the initial reporter identity fields on Form FDA 3500A with a statement such as “Requested Anonymity…If an adverse event is reported anonymously to an outsourcing facility, the outsourcing facility should note when submitting the report to FDA that the initial reporter is anonymous (section E1 of the Form FDA 3500A).”

Comment: Again good to know how to handle this.

Suspect Drug

This section, again aimed at the compounded products, notes that the “product attributes” including active ingredient(s), dosage form, strength, color, lot) should be included. If the report involves more than one compounded product from the same compounder, submit only one report. The draft goes on to give details on how to handle this. See the document for further information.

Comment: This is, presumably, more important for compounded products than usual drug products. Rarely do companies obtain color, lot numbers etc. for routine SAEs. FDA should clarify this in the final regulation.

Serious Adverse Event

This section reviews the well-known definition of serious and notes that “inpatient hospitalization includes initial admission to the hospital on a inpatient basis (even if released the same day).”

The FDA then states: “For reporting purposes, an adverse event should be described in terms of signs (including abnormal laboratory findings, if appropriate), symptoms, or disease diagnosis (including any colloquial descriptions obtained), if available.”

Comment: This last paragraph actually further defines an SAE: An SAE can be an abnormal sign, lab values or disease diagnosis. Not a surprise but good to see it spelled out.

FDA encourages (but evidently does not require) the “attachment” of: (1) hospital discharge summaries, (2) autopsy reports/death certificates, (3) relevant laboratory data, and (4) other critical clinical data. In the case of a death, outsourcing facilities should also provide any available information on the event(s) that led to the death.”

Comment: Presumably the lab values and critical clinical data can be included in the narrative case summary rather than as formal attachments. This is how most companies normally do it.

How to Report

FDA describes the use of the MedWatch 3500A form and the details of how to submit. FDA notes they are working on setting up electronic submission but this is not permitted yet. See this section for full details, addresses, email addresses, phone numbers etc.

Inspections of AE Reporting

FDA notes that outsourcing facilities (and per the regulations sponsors and other firms) are subject to inspection. FDA may review AE information and whether the facility has developed and implemented written processes for the surveillance, receipt, evaluation and reporting of AEs…”

Comment: All of this is well known. There is a nuance here though. A firm must have written SOPs (standard operating procedures/processes) but must also implement them. It’s not enough to just have them but one must show that the staff has received them, been trained and has put them into use.

Overall Comment: No major surprises but good to see FDA’s thoughts all put into one place. One suspects that there may be some comments (this is a draft guidance and comments are being solicited by FDA) to the effect that clarification would be useful as to whether these comments should apply to other situations beyond compounded products.


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