US FDA Recognizes Eight EU Authorities, Triggers Mutual Recognition Provisions

US FDA recognizes the drug regulatory authorities for eight of the European Union's 28 member states by a Nov. 1 deadline, triggering key provisions of the landmark mutual recognition agreement.

The US FDA has named the first eight European drug regulatory authorities that it is recognizing under a US/EU mutual recognition agreement reached in March.

It will now be the exception rather than the rule for FDA to inspect pharmaceutical manufacturing facilities in these countries: Austria, Croatia, France, Italy, Malta, Spain, Sweden and the UK.

FDA will henceforth determine compliance status based on domestic inspection findings of authorities in those countries. However, the determinations it makes based on those findings won't necessarily mirror the decisions of foreign authorities.

FDA's recognition of the eight countries on Oct. 31 meets a Nov. 1 deadline that triggers key provisions of the agreement, most notably the EU's recognition of FDA's domestic inspection findings. However, EU inspectorates already had begun to defer US inspections in anticipation that FDA would meet the deadline. (Also see "EU To Defer US GMP Inspections Ahead Of Mutual Recognition Agreement Becoming Operational In November" - Pink Sheet, 27 Jun, 2017.)

The EU had recognized FDA in June and added the agency to its list of recognized authorities on Aug. 11. A separate Aug. 23 agreement with the European Commission enabled FDA to share commercially confidential information with its European counterparts. No longer will the agency have to redact such information from inspection reports before sharing them with EU authorities. (Also see "EU, US Commit To Sharing Full Inspection Reports To Supplement GMP Mutual Recognition" - Pink Sheet, 24 Aug, 2017.)

FDA must recognize the other 20 EU member states by July 15, 2019, for the mutual recognition agreement to remain in effect.

The agreement will apply to each European country as FDA recognizes them. It is unclear when these recognitions will occur or to what extent they will be announced.

Agency Leaders Laud Milestone

Agency leaders on both sides of the Atlantic provided written statements lauding the latest development.

FDA Commissioner Scott Gottlieb emphasized the importance of the agreement in enabling the agency to focus more inspectional resources on higher-risk countries, while Guido Rasi, executive director of the European Medicines Agency, noted that this is the EU's sixth such agreement with third-country parties. Dara Corrigan, FDA’s acting deputy commissioner for global regulatory operations and policy, and a chief architect of the agreement, called it an "unprecedented and significant step."

Ellen Morrison, assistant commissioner for medical products and tobacco operations in FDA's Office of Regulatory Affairs, Oct. 31 told the annual meeting of the International Society for Pharmaceutical Engineering in San Diego, California, "we are excited about this. The agreement will allow regulators to use inspection reports to help determine whether facilities are making high-quality drugs."

In response to a question, Morrison said FDA's addition of Germany to the agreement is "still under discussion." Corrigan and others have called attention to the complexity of evaluating Germany due to the provincial nature of its inspectorate. Morrison said, "we hope it's going to be this year."

Key Provisions Triggered

Some aspects of the revised mutual recognition agreement took effect March 2, the day after its signing was completed. (Also see "EU, US Finally Agree On Mutual Recognition Of GMP Inspections" - Pink Sheet, 2 Mar, 2017.)

Other aspects took effect Nov. 1, when the agreement became operational, such as the cessation of routine inspections by EU authorities in the US and routine FDA inspections in the first eight EU countries the agency has recognized.

By meeting the Nov. 1 deadline, FDA triggered four key articles of the agreement, which was incorporated as an amended pharmaceutical sectoral annex to a 1998 mutual recognition agreement between the US and the EU. (Also see "Why Now Is The Right Time For Mutual Recognition" - Pink Sheet, 3 Mar, 2017.)

These articles require the parties to accept each other's inspection findings, though with some exceptions, as well as share GMP documents, request inspections, and continue to assess each other.

Article 8: recognition of inspections. This article requires the parties to accept "official GMP documents" concerning domestic facilities of recognized authorities, which means relying on the document's factual findings.

However, there are exceptions. An authority can decline to accept GMP documents because an inspection report appears to have "material inconsistencies or inadequacies," or is overshadowed by evidence of quality defects or consumer safety issues arising from post-market surveillance or complaints.

The declining authority must explain why it won't accept the report and request clarification. The authority that produced the GMP documents must respond, typically based on input from members of its inspection team.

Article 10: transmission of official GMP documents. This article sets forth a process for sharing GMP documents. It gives an exporting country's authority 30 days to share such documents with the importing country, if requested. If the importing country determines, based on its review of the GMP documents, that a new inspection is in order, it can request one per Article 11.

Article 11: requests for pre-approval and post-approval inspections. This article sets forth a procedure for requesting pre-approval and post-approval inspections.

An authority that receives such a request gets 15 days to say whether it will do the inspection. Such requests would most likely arise in the context of an application for marketing approval or of information warranting for-cause inspections.

If the requested authority believes it has relevant GMP documents, it should alert the requesting authority and provide the documents upon request.

Article 12: maintenance. This article calls for regular audits or assessments of each authority to make sure it continues to merit recognition.

From the editors of the Gold Sheet.