Posted: April 2017
*Erik T. MacLaren, PhD, is acknowledged for his editorial support of this article.
On March 2, 2017, the European Union (EU) and the US announced the Mutual Recognition Agreement to allow the FDA and the EU to accept one another’s inspections of drug and pharmaceutical manufacturing facilities, a change intended to reduce duplicated effort with European inspectorates and to more efficiently monitor the global drug supply. Known as the 2017 Amended Sectoral Annex, this agreement grew out of the Mutual Reliance Initiative that launched in 2014 and allowed the FDA and EU to evaluate each other’s drug inspection processes. Dara Corrigan, JD, the FDA’s Acting Deputy Commissioner for Global Regulatory Operations and Policy described the purpose and potential impact of the Mutual Reliance for IASLC Lung Cancer News readers.
Q: What need does the Mutual Reliance Initiative address?
A: Strengthening use of the FDA and EU drug inspection expertise and resources will result in greater efficiencies for both regulatory systems, and will provide a more practical means to oversee the large number of drug manufacturing facilities outside of the US and the EU. Until now, the EU and the FDA sometimes would, in the same year, inspect some of the same facilities, even when the facilities had a strong record of compliance. With the 2017 Amended Sectoral Annex, such duplication should be the exception. By utilizing each other’s inspection reports and related information, the FDA and EU will be able to reallocate resources towards inspection of drug manufacturing facilities across the globe that have potentially higher public health risks.
The scope of the Amended Sectoral Annex covers a broad range of human drugs and biologics, as well as veterinary drugs, and does have specific exclusions. Current good manufacturing practices (GMPs) inspections of facilities that are manufacturing vaccines and plasma-derived products are not immediately included within the scope of the agreement. The possibility of including vaccines and plasma-derived products will be re-evaluated no later than July 15, 2022. Human blood, human plasma, human tissues and organs, and veterinary immunologics are not included within the scope of the Amended Sectoral Annex.
Q: How has the growth pattern of drug manufacturing affected the distribution of needed pharmaceutical agents?
A: The FDA inspects drug manufacturing facilities that make drugs for US consumers. Similarly, regulatory agencies in other nations inspect facilities that make drugs for their citizens. Currently, a large percentage of the FDA’s foreign drug manufacturing facility inspections are conducted in the EU. Because the number of manufacturing facilities around the world is growing, the FDA uses a riskbased approach to focus inspection resources on those facilities with the highest potential risk. This surging growth of foreign drug manufacturing facilities, particularly in China and India, has had ramifications for the FDA’s approach to inspections of drug manufacturing facilities that are overseas. Within the current risk-based approach, the FDA has steadily increased foreign surveillance inspections overall. However, we can be more strategic and efficient in using our limited resources to manage this shift of drug facilities to foreign territories. One way of doing so is to identify partners with capable inspectorates so we can share the hard work of overseeing drug manufacturing for the global market, thus ensuring that our patients receive quality drugs that are safe and effective.
If the FDA is able to rely on inspections conducted by the EU regulatory agencies, then we can shift our drug inspection resources from the EU to other manufacturing locations and facilities and increase coverage of drug manufacturing facilities that pose a higher risk to US patients. This will allow the FDA to be better able to identify drug quality problems earlier and prevent poor-quality drugs from entering the US market.
Since 2012, an average of 41% of the FDA’s inspections of foreign drug manufacturing facilities have been conducted in the EU, compared to 13% in China, 19% in India, and 27% in the rest of the world (excluding the US). Over 80% of drug ingredient manufacturers registered with the FDA are located outside of the US.
Q: What is the background to the Mutual Recognition Agreement?
A: The amended Sectoral Annex builds on the 1998 Agreement on Mutual Recognition between the European Community and the United States of America (U.S.-EU MRA), which included a Pharmaceutical Annex relating to GMP inspections. It benefits from the collaboration of the EU and the US in the past years through various pilot initiatives on GMP inspections. In 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). This law gave the FDA authority to enter into agreements to recognize inspections conducted by foreign regulatory authorities, if the FDA determines that these authorities are capable of conducting inspections that meet US requirements. This new law, combined with our previous experience, enabled us to successfully negotiate the amended Sectoral Annex. The 2017 amended Sectoral Annex to the 1998 U.S.-EU MRA allows FDA and EU inspectorates to use inspection reports and other related information obtained during drug manufacturing facility inspections, whether conducted by an EU inspectorate or by the FDA, to help determine whether a facility is manufacturing high-quality drugs. Then, if necessary, the FDA or EU can require further inspections or take other action to protect the public.
Q: Why have previous efforts to reach this type of agreement failed and why did the present program succeed? Is this an accurate characterization?
A: The Pharmaceutical Annex of the U.S.-EU MRA was never fully implemented for various reasons, including lack of dedicated resources. There were outstanding information gaps regarding how the FDA and EU systems compared, and no clear path forward on how to implement the Annex. Although the MRA was agreed between the US and the EU, the FDA will conduct an assessment of each EU country’s regulatory authority individually. The FDA is currently assessing 5 regulatory authorities, and anticipates reaching a final decision on 8 EU regulatory authorities by November 1, 2017. The capability assessments of all EU countries’ inspectorates are scheduled to be completed by July 15, 2019.
Q: What is the real or potential impact of the MRA on patient care?
A: This MRA will further enhance the FDA’s ability to prioritize inspections of drug manufacturing facilities that may pose higher risks to public health. This prioritization will help the FDA to identify potential drug quality problems more quickly and prevent poor quality drugs from entering into the US market, thereby benefiting patients and reducing adverse public health outcomes.
Conclusion
Overseas pharmaceutical manufacturing presents a growing challenge to the FDA’s capacity to monitor the quality and safety of imported drugs. The MRA represents a new strategy to find efficiencies in the inspection process so that more resources can be allocated to regions presenting greater risks. Although a first for the FDA, the EU already has MRAs in place with Australia, New Zealand, Japan, and Switzerland. Asked what the future holds now that the Pharmaceutical Sectoral Annex has been amended, Ms. Corrigan said that the FDA will implement the agreement and continue to work collaboratively with trusted regulators in non-EU nations to evaluate whether mutual recognition agreements will provide similar benefits to public health. ✦
