The U.S./EU mutual recognition agreement (MRA) is bearing fruit in the form of inspections being performed by partner agencies accepted by the other MRA agencies in lieu of performing inspections themselves. For example, the U.S. FDA has received over 200 inspection reports from European health authorities and deferred nearly as many European inspections.
At the inaugural PDA Europe Aseptic Animal Health conference held virtually in October 2020, FDA Office of Regulatory Affairs (ORA) Supervisory Consumer Safety Officer Susan Laska provided an update on her agency’s MRA with European countries and the status of veterinary products in the agreement.
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History of the U.S./EU MRA
The current MRA has roots in the existing 1998 agreement on mutual recognition between the European community and the United States. “Many of you may recall that back in the late nineties, there was some initial work that was done on the agreement, but that was quickly put into abeyance,” Laska said.
The 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) included provisions allowing the agency to enter into agreements with foreign health agencies, which facilitated initiation of work on the current MRA.
Title VII, Section 712 of FDASIA allows for written agreements to be entered into and for the agency to recognize the inspection of foreign drug establishments for the purpose of facilitating its risk-based surveillance schedule. Such agreements can be acted on once the foreign government has been deemed capable. In 2014 work began in earnest to get the current agreement in place. The implementation date was November 1, 2017.
One key milestone in this process is the December 2019 decision that veterinary medicines can be included. “Keep in mind the initial scope of the agreement was for human pharmaceuticals,” Laska reminded conference attendees. “One of the many future milestones in the agreement was a milestone to evaluate veterinary medicines.”
The pharmaceutical annex to the 1998 agreement is the basis for the current agreement. It cements the FDA and European Union collaboration by taking concrete steps to rely upon each other to benefit public health. It enables FDA to share its inspection resources to avoid duplication of drug inspections and devote those “precious” resources to facilities where there may be a greater risk, Laska commented.
Scope and Benefits of the U.S./EU MRA
The benefits of the MRA, Laska said, have been magnified by the COVID-19 pandemic. “The current public health crisis that we are in has really emphasized the benefits of having such agreements in place.”
On March 11, 2020, FDA announced that it was postponing foreign surveillance inspections. On March 18, it announced that it was postponing routine surveillance domestic inspections. “The benefits of the agreements that we have in place to provide greater efficiency of coverage of facilities that are shipping products into the U.S. have been remarkable,” Laska commented.
One of the many future milestones in the agreement was a milestone to evaluate veterinary medicines
Products that are in scope include marketed finished pharmaceuticals for human use, active pharmaceutical ingredients, allergenic products, and therapeutic biotech derived biologicals— well-characterized recombinant products.
In addition, there are milestones and products that will be considered in the future. These include vaccine products and the inclusion of other types of inspections such as preapproval inspections. Currently, only surveillance inspections for human drug facilities are in scope.
There are several major deliverables in the agreement resulting from the work that has been done since 2017.
The agreement was signed in January and March of 2017. That July, the European Union completed its assessment of the U.S. FDA for oversight of human pharmaceuticals, deeming it a capable agency. In November 2017, FDA announced its decision on the first eight authorities and a November implementation date for the agreement on human pharmaceuticals. FDA announced in July 2019 that it had completed the assessment for all 28 authorities (Figure 1).
In the future the following product and inspection types may be included in the coverage of the agreement, pending further consideration: vaccines for human use; plasma derived pharmaceuticals; and investigational products (clinical trial material). Excluded from the MRA scope are human blood, human plasma, human tissues and organs and veterinary immunological products.
In December 2019, there was an announcement that veterinary products, beginning at that time, are included within the scope of the MRA. A decision on vaccines and plasma-derived pharmaceuticals is expected by July 2022.
Inspectorate Capability Assessed by FDA
“A lot of work goes into the capability assessments,” Laska stressed. “Determining the inspectorate capability is a very comprehensive process.”
For FDA, multi-disciplinary, multicenter teams evaluate each authority, including the field inspectorate and subject matter experts. In looking at the foreign regulatory authority, FDA needs to determine whether the agency has responsibility over the appropriate industries and can do the work FDA wants it to.
The following questions are explored as part of the assessment of the foreign agencies:
- Do they have the legislation?
- Do they have strict rules on conflict of interest? FDA observes them conducting inspections.
- How are the inspections conducted?
- Are the quality systems evaluated?
FDA also looks at the training of the inspectorate, including how they are trained, whether there is a curriculum, and if so what it consists of. It also looks at the requirements to be part of the inspectorate.
The agency has been busy since December of 2019 on completing the assessments for the authorities with oversight of veterinary medicine. Keep in mind when it came to human pharmaceuticals there were 28 authorities, when it comes to oversight of veterinary medicines it introduces 14 new authorities. As mentioned, those assessments are underway and that work is a priority for the agents.
Impact of the U.S./EU MRA
All foreign human drug authorities were deemed capable in July 2019.
FDA has asked European agencies to conduct 78 inspections on its behalf. “In other words,” Laska said, “these were sites that we were extremely interested in. The sites came to the top of our risk model and we had asked EU to conduct those inspections on our behalf.”
The EU in turn has asked FDA to conduct 21 inspections. In addition, FDA deferred 172 inspections in the EU. “This allowed our investigators to inspect in other high-risk areas,” Laska pointed out. In addition, FDA has provided 97 inspection reports to the European Union for it to use for its own compliance decisions (Figure 2).
“Part of the agreement is that we at FDA review inspection reports” (Figure 3). “It is important in our system that we review what was covered during an inspection. Was it the product systems, for example, that are of interest to the US? Reviewing the reports enables and allows for each authority to take their own compliance and enforcement actions” Laska reported.
One “bright spot,” the 2020 COVID-19 pandemic is reinforcing according to Laska is collaboration among the regulators. This year alone, US FDA has requested 235 reports of inspections conducted by European authorities. 167 of those inspections have been classified.
Part of the review of a report is to determine what was covered and what potential impact any deficiencies had on product. In addition, was the coverage sufficient for the products that are being shipped into the US? All that goes into the review of inspection reports regardless of whether the inspection was conducted by a US FDA investigator or it was conducted by an inspector from a European capable authority.
“During this time of restricted travel there have been increased requests and review of completed inspections in third countries—inspections not in Europe, but where the European capable authority has inspected in another part of the world. In other words, facilities that are of interest to FDA in other non-EU parts of the world. FDA has been utilizing the inspections from capable authorities in those third countries and that work continues.”
In closing, she emphasized that work continues on the assessment of veterinary medicinal authorities.
[Related: Test drive our Enforcement Analytics platform and see how Redica Systems can help you prepare for your next inspection.]
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