Letters have been exchanged and the full agreement could enter into force in November.
The U.S. and the European Union (EU) have completed an exchange of letters to amend the Pharmaceutical Annex to the 1998 U.S.-EU Mutual Recognition Agreement (MRA). The full text is available on the European Commission (EC) website.
This brings to fruition a long-delayed process by which regulators on either side of the Atlantic will accept GMP inspections of pharmaceutical manufacturing facilities by each other’s regulatory authorities: the FDA in the U.S. and national competent authorities of Members States, coordinated by the European Medicines Agency (EMA), in the EU.
Once this agreement is fully in force, U.S. authorities will only have to visit EU facilities in exceptional circumstances and vice-versa. They will also be able to accept each other’s inspections of facilities in other countries, which both sides see as a vital boon when the vast majority of APIs consumed on both continents are manufactured in Asia.
About 40% of the finished medicines marketed in the EU come from outside the EU and 80% of the manufacturers of APIs for medicines available there are also located outside it. The proportions are believed to be roughly similar in the U.S. In practice, many of the facilities were rarely or never inspected, leaving many gaps for unscrupulous suppliers to exploit.
The FDA said that the agreement will enable it and the EMA “to avoid the duplication of drug inspections, lower inspection costs and enable regulators to devote more resources to other parts of the world where there may be greater risk”. The MRA, added Dara Corrigan, FDA’s Associate Commissioner for Global Regulatory policy, “is an important step in working collaboratively and strategically with key partners to help ensure that American patients have access to safe, effective and high quality drugs”.
According to the EC, the agreement “facilitates the exchange of official GMP Documents” and increases “reliance on the factual findings in such document”. It added: “The enhanced co-operation with U.S. regulatory authorities will improve the EU’s ability to identify and address problems at factories before they become a public health risk. It will also reduce the administrative burdens and costs facing pharmaceutical manufacturers, including smaller producers”.
The original MRA of 1998 had not yet been implemented, though many of its provisions are in force and others, now including recognition of inspections, are scheduled to enter into force on November 1 2017. By that date, the EMA said, “the EU will have completed its assessment of the FDA and the FDA is expected to have completed its assessment of at least eight EU Member States, and will be gradually expanded to all Member States”.
The two agencies had gradually shifted towards closer collaboration since 2009, when they launched a GCP initiative. This introduced information-sharing and collaborative inspections for the first time. It was later expanded to non-EU, non-U.S. sites. A GMP inspection program for API-manufacturing facilities was introduced later in the year and was extended to finished dosage form manufacturing plants in 2011.
Another step forward was taken in 2012, when Congress passed the FDA Safety & Innovation Act. This authorized the agency to concluded agreements to recognize drug inspections conducted by foreign regulatory authorities if it determined them to be capable of conducting inspections that met U.S. requirements.
Beginning in May 2014, the FDA and the EMA have collaborated to evaluate the way they each inspect drug manufacturers and assessing the risk and benefits of mutual recognition. Since then, the FDA has observed 14 audits of the inspectorates of Member States by those from two others. The EMA said that this joint work has thrown up “robust evidence on both sides of the Atlantic that the EU and the US have comparable regulatory and procedural frameworks for inspections of manufacturers of human medicines”.
It is likely that mutual recognition could be extended further in the developed world in the longer term, given that the EU already has MRAs for GMP inspections with several other countries, including Australia, New Zealand, Canada, Japan and Switzerland. Norway, although not an EU Member State, follows the EMA inspection regime and it is very likely that the UK will continue to do so post-Brexit.