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In October 2015 FDA released a guidance on AE Reporting for Outsourcing Facilities Under Section 503B of the FDC Act.

This is a 10-page document that covers FDA’s view on the Drug Quality and Security Act (DQSA), which was signed into law in November 2013 and added section 503B to the Food, Drug and Cosmetic Act.  This section requires compounders (“an outsourcing facility”) to send adverse event reports to the FDA.

The issue here largely revolved around the fact these products did not have an NDA or ANDA in place and thus there was no clear obligation to report SAEs.  In addition, over the last few years, there have been some scandals involving quality issues with contaminated products from compounders and a dispute in regard to jurisdiction between the FDA and state agencies.

The new section now adds “prescription drug products” that are compounded to products where serious, unexpected ADRs associated with the use of the products must be reported to FDA.  It notes that these reports must be made whether or not the outsourcing facility distributes them “pursuant to prescriptions”.

In addition, the June 2014 requirement that post-marketing safety reports be submitted electronically is also required for these reports.

FDA stresses that reportable cases are not just those of quality issues but also a “side effect,” lack of efficacy, the patient’s underlying condition or concomitant medication use.

It is interesting that FDA uses the term “side effect” in this guidance. The term “side effect” is now considered by most in the PV world to be outmoded and non-scientific though everyone in medicine and in the public recognizes the term as referring to a bad thing happening with drugs. A triumph of clarity over jargon!

Nonetheless, the main issue here is quality and FDA wants to improve the mechanism to pick up quality problems that may have been caused by substandard conditions or processes in manufacture. The need to differentiate these from medication errors, procedural issues in hospitals or pharmacies or problems with the ingredients (active moieties or excipients) is also a goal of the new requirement.

FDA defines the usual terms (serious, unexpected etc.)  from 21CFR310.305. There are no surprises with these definitions.

The reporting requirement is, as expected for post-marketing products, that all serious unexpected ADRs be reported in 15 calendar days and follow up be done to get complete information. The guidance specifically states that information on the names and addresses of individual patients not be included for privacy reasons.  Firms must maintain records for 10 years.

In the guidance, FDA recommends, but notes that it is not obligatory, that all SAEs associated with their products be reported, not just those that are unexpected.

One small surprise, though, is that after FDA defines the usual four minimum criteria for a valid report (patient, reporter, suspect drug, SAE), the FDA notes, in bold letters: “Reports should be submitted as long as the outsourcing facility has information on at least the suspect drug and adverse event.” Thus, FDA has lowered the threshold for reporting.

The tricky area involves the suspect drug product. Here FDA wants as much information as possible (e.g. active ingredient(s), dosage form, strength, color, lot number). If an AE case has multiple suspect drug products compounded by the same manufacturer, only one report should be sent with the most suspect product listed as the suspect drug product. The report should contain all the products/compounds and probably excipients in the product(s).

In the submission, the current labeling must be included. The company is encouraged to include any other additional medical information or reports (if available) such as hospital discharge summaries, autopsies, lab data etc.

There is information on the electronic submission. See the guidance for the details.

Finally, FDA notes that such facilities may be inspected by the FDA looking at AEs and whether the facility has developed and implemented written SOPs for surveillance, receipt, evaluation and reporting of AEs. In other words, they will treated like any pharma manufacturer or company.


This is a very reasonable guidance clarifying what was a murky and political hot potato after the problems with contaminated products several years ago. Compounders now must set up and maintain drug safety/PV functions either in-house or outsourced. There should be clinicians involved to review the cases and, ideally, a physician to review all serious AEs. Given the history around these issues, such facilities should expect FDA inspections sooner rather than later.


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