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On December 15, 2012 FDA issued its updated Chapter 53 on Postmarketing  Adverse Drug Experience (PADE) Reporting Instructions.  This is part of FDA’s Compliance Program Guidance Manual but is, in reality, more or less an SOP for FDA’s inspectors. Although there is nothing really new, it is worth reading to review what FDA will look for during an inspection of your company or a vendor handling drug safety and/PV.  You can obtain it at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM332013.pdf?source=govdelivery

We’ll give a summary of some of the key points here.  Much of the content explains the interactions between the PV Compliance Team in the Office of Compliance and the Office of Scientific Investigations.  If you are interested in these internal FDA interactions, please see the document as we’ll not cover them here.

The document also summarizes the regulations we are all familiar with for the FDA investigators and, again, no real surprises here.  The reporting covers primarily expedited reporting and periodic reporting plus the requirements for manufacturers, packers or distributors whose names are on the label or package to report SAEs to FDA or the NDA/ANDA holder.

The objectives of an FDA inspection include the assurance that safe and effective drugs are available to the US public, to verify the accuracy, reliability and timeliness of postmarking data submitted to FDA, to support medical reviews by FDA and to monitor industry’s compliance with regulatory requirements.

The concept of the “responsible firm” is defined as holders of NDAs, ANDAs and the manufacturer, packer, or distributor on the label of approved drug products, non-application prescription or OTC drugs (that is, drugs without an ANDA or NDA) and any person holding a biologics license.  The message here is that even if you use vendors or sub-contractors, you (the NDA/ANDA holder) are responsible for drug safety.

FDA will select, each year, firms to be inspected using a risk based approach.  This approach is based on the firm’s past compliance history, identified deficiencies, and recently approved NDA/ANDAs, concerns coming from another office of the FDA and District Offices.

The focus may be non-specific or may be on specific drugs if there are issues such as incomplete safety profiles (drugs approved within the last 3 years), products with postmarketing requirements or commitments, safety study obligations or REMS.  In addition products with pediatric or vulnerable populations, narrow therapeutic index or known safety risks will be examined.

There are many specific instructions for inspectors.  For example, the inspector will ask for a complete list of the firm’s products (approved, unapproved, Rx, OTC) with their regulatory approval details.  Drugs marketed outside the US may be looked at if they contain the same active moiety as drugs marketed in the US (not necessarily by the firm being inspected).

There is much emphasis on written procedures (SOPs).  They must be complete, accurate and ensure timely reporting to FDA.  They must be easily available and followed by all employees involved in PV and all those who may come into contact with potential AE information (including legal staff, administrative support staff, sales representatives, professional and consumer information support staff, and contractors). They cover all the processes in PADE handling as well as how cases are handled after normal business hours, electronic sources of cases (e.g. email, website comment boards). SOPs must cover spontaneous (non-solicited) as well as study and solicited cases (e.g. clinical trials, patient registries, pregnancy registries, company sponsored patient support programs, disease management programs, or postmarketing studies). Interestingly, they note the fact that OTC monograph drug reporting does NOT require written SOPs.  (Not quite sure why this should be but that is the way the regs are written.  A wise OTC company will still have written SOPs even if not absolutely required.).

The inspector should be sure that a mechanism is in place to ensure that all of the firm’s employees who could foreseeably come into contact with postmarketing AEs should be able to identify an AE, know the four basic elements for reporting and how to convey the AE information to the firm’s PV department.

The inspector should review the firm’s procedures for determining how information is extracted from the source documents and entered into the reports submitted to FDA such that all pertinent information is included.  He or she should review representative ICSRs compared to the source documents.

Individual cases should be reviewed covering the usual items: seriousness, expectedness, MedDRA coding, timeliness of 15 day expedited reports.  The inspector is instructed to ask for a listing of all late 15 day cases, the reason for their lateness and the corrective actions put in place. Obviously, this is a clear signal to firms to have this list ready and that a root cause analysis be done for each late report and a CAPA put in place if needed.

The inspector is requested to obtain copies of cases and source documents and convey them to the FDA PVC team if relevant data is omitted from or misrepresented in a report submitted to FDA.  Obviously, this will be looked at very severely by FDA.

If waivers for non-submission of some cases, changes in timeframes for submission, PSURs instead of PADERs, exemption from non-serous labeled AE reporting are in place the inspector is to obtain a copy and review them to be sure the cases are handled per the waiver.

Follow up procedures must be in place to collect all needed data.

It is clearly explained that cases from postmarketing studies (defined broadly as patient registries, pregnancy registries, company sponsored patient support programs, disease management programs etc.) are expedited if they are serious, unexpected and there is a reasonable possibility that the drug caused the AE.  The firm must identify, monitor and track all such studies to ensure that AEs are properly handled.  The firm must examine all AEs associated with the use of its drug even if the drug is not the primary study drug (e.g., is used as a concomitant medication or as the comparator product in a study).  Study information must be included in PADERs and NDA annual reports.

Expedited (alert) 15 day reports must be examined and the procedures in place to handle them (including causality where required) reviewed.

There is a large section covering safety data exchange agreements.  This is new and really did not appear in the previous version of this document.  The inspector must review agreements between the firm and any other manufacturers, packers, distributors, affiliates, subsidiaries, contract research organizations (CROs), licensees, or parent companies to determine if the agreement adequately addresses the firm’s PV and PADE reporting activities and regulatory responsibilities.  The inspector should verify that the agreements meet regulatory requirements and that the firms are following the agreements. Contractors and vendors must have agreements in place and written SOPs. (This is an area FDA, EMA and other inspectors and auditors now pay a lot of attention to.  Firms really need to have this in control).

An interesting area not covered in the regulations but discussed here is “corporate transitions”.  This refers to the transfer of drug approvals, the transfer of PV activities, corporate mergers, corporate restructuring, large scale personnel changes, or significant information technology (IT) changes such as new computer systems or databases.  These are red flags for the inspectors who should determine that written SOPs have been appropriately updated to ensure that the surveillance, receipt, evaluation, and reporting of PADEs remains in a state of compliance. (If you have had such a transition, you’ll likely be inspected soon).

Special distribution systems such as patient assistance programs and product sampling programs must have written procedures in place to ensure AEs are handled correctly.

Foreign (ex-US) cases that are serious and unexpected are expedited reports but other foreign reports, including serious and expected, non-serious and unexpected, and non-serious and expected AEs are not required to be submitted to FDA.  An interesting point that FDA notes is that reports of foreign serious, unexpected AEs should be submitted for products that have the same active moiety as a product marketed in the US. This is true even if the excipient, dosage forms, strengths, routes of administration, and indications vary.  In my experience, not all firms do this.  It has to be done.  The foreign report should have its product information clearly noted in the MedWatch form.  The clock start is when the foreign affiliate, vendor etc. first receives the case.

Cases received by a company’s legal department (usually as lawsuits or class actions) are, of course, subject to FDA reporting and adequate written SOPs must exist in the firm to cover this.  If firms obtain waivers from FDA to alter reporting obligations or timelines, the inspector should get the waiver and review the firm’s compliance to it.

Scientific literature reports should be reviewed.  All serious unexpected cases must be submitted in 15 days along with a copy of the article in English.

Product complaints will be reviewed by the inspector.

PSURs/PADERs should be reviewed for timeliness, completeness and whether they are submitted electronically or on paper.  Note that no periodic reports are required for OTC and Rx products without an approval.  OTC monograph reporting is to be reviewed.

Electronic submissions are to be treated, in terms of timeliness, as if they were paper submissions.  All 21CFR requirements must be adhered to.

There is a long section on out-sourcing.  This is new as no such section appeared in the previous version of this document.

–  If the firm is reluctant to do this, tell the firm that they may redact any financial information in the contract. During PADE inspections, the Agency is interested in scope of work only.

–  Non-applicant manufacturers, packers or distributors who do not submit serious and unexpected PADEs to the applicant within five calendar days, are required to submit them to the Agency within fifteen (15) calendar days.

The FDA is fairly explicit now in the criteria for a Warning Letter (WL):

FDA also refers to “Untitled Letters” (UL).  This is a letter to a firm when deficiencies are found that are severe enough to justify a formal letter but not quite at the level of a Warning Letter.

Responses and CAPAs to 483s, WLs and any other communication from FDA are now expected and required.  They will be reviewed and monitored at the District Office.  If they are inadequate the District Office will begin follow up.  This includes communications and further inspections.  The District Office can raise the issue to FDA headquarters if warranted.  Finally, FDA talks of injunctions, seizures and prosecution for failure to comply with required corrective actions.


 No real surprises here but FDA is, as always, taking inspections VERY seriously.  Responses are expected and will be monitored if you make commitments or promises to FDA.  Consequences can be severe for failure to do what is promised.  The lessons (also obvious) that one should draw are basically two:

  1. Keep your drug safety/PV in ship shape condition
  2. Be ready for an inspection (unannounced) at any time.

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