By Mark I. Schwartz –
Last week, the United States and the European Union agreed to recognize each other’s drug cGMP inspections. The agreement reached (see here and here) amends the Pharmaceutical Annex to the 1998 U.S. – E.U. Mutual Recognition Agreement, with a view to avoiding duplicative inspections and saving millions of dollars in repetitive inspections.
FDA has stated that they believe this “…initiative will result in greater efficiencies for both regulatory systems and provide a more practical means to oversee the large number of drug manufacturing facilities outside of the U.S. and EU.”
Until now, the EU and FDA sometimes would inspect some of the same facilities within a brief period of time. With this new agreement, such duplication is expected to be the exception, rather than the rule. “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 with potentially higher public health risks across the globe. This will benefit patients and reduce adverse public health outcomes.”
Interestingly, many, if not most, products regulated by the Center for Biologics Evaluation and Research at FDA appear to fall outside the ambit of this agreement (as do veterinary immunologicals). “Current good manufacturing practices (CGMPs) inspections of facilities 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, [and] human tissues are not included within the scope of the Amended Sectoral Annex.”
As some of our readers may recall, we blogged about the negotiations regarding the Mutual Reliance Initiative last summer, here, where we stated that the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) allows FDA to enter into arrangements with foreign governments to recognize the inspection of foreign establishments that are registered under the FDCA “…in order to facilitate risk-based inspections…”
FDASIA section 712 (FDCA section 809):
(a) INSPECTION.—The Secretary—
(1) may enter into arrangements and agreements with a foreign government or an agency of a foreign government to recognize the inspection of foreign establishments registered under section 510(i) in order to facilitate risk-based inspections in accordance with the schedule established in section 510(h)(3);
(2) may enter into arrangements and agreements with a foreign government or an agency of a foreign government under this section only with a foreign government or an agency of a foreign government that the Secretary has determined as having the capability of conduction inspections that meet the applicable requirements of this Act; and
(3) shall perform such reviews and audits of drug safety programs, systems, and standards of a foreign government or agency for the foreign government as the Secretary deems necessary to determine that the foreign government or agency of the foreign government is capable of conducting inspections that meet the applicable requirements of this Act.
(b) RESULTS OF INSPECTION.—The results of inspections performed by a foreign government or an agency of a foreign government under this section may be used as—
(1) evidence of compliance with section 501(a)(2)(B) or section 801(r); and
(2) for any other purposes as determined appropriate by the Secretary.
The Mutual Recognition Agreement defines an inspectorate that is capable of conducting an inspection of a drug manufacturing facility that meets U.S. requirements, as one that:
- has the legal and regulatory authority to conduct inspections against a standard for GMP;
- manages conflicts of interest in an ethical manner;
- evaluates risks and mitigates them;
- maintains appropriate oversight of manufacturing facilities within its territory;
- receives adequate resources and uses them;
- employs trained and qualified inspectors with the skills and knowledge to identify manufacturing practices that may lead to patient harm; and
- possesses the tools necessary to take action to protect the public from harm due to poor quality drugs or medicinal products.
However, according to FDA, the term “capable” does not require that the inspectorate maintain procedures for conducting inspections and overseeing manufacturing facilities that are identical to the FDA's procedures.
As we stated last summer, the notion of having a foreign inspectorate perform drug inspections on FDA’s behalf, when the inspections performed by FDA’s own investigators are already so inconsistent, is problematic at best. Indeed, FDA representatives have long acknowledged that the agency doesn’t have an objective method for measuring quality in the drug industry (for instance, at which facilities are cGMPs improving? By how much and in what way?) Nor do they have a reliable method for making cGMP comparisons between facilities manufacturing similar products, or for comparing the results from within a facility over multiple inspections. (This author will acknowledge that the agency has published a draft guidance on Quality Metrics, which has yet to be finalized, and it is also developing a New Inspection Protocol Project, both of which seek to remedy these weaknesses in the agency’s inspection process. However, these projects are in their earliest stages, they remain largely untested, and it is unclear at this point whether they will lead to more consistency in inspectional results.)
It would seem that rectifying these significant lacunae in FDA’s inspectional responsibilities should be the first order of business for the agency, prior to even considering delegating the responsibility for EU inspections to a foreign inspectorate which is not schooled in FDA’s precise cGMP requirements, and is not required to maintain the same procedures as FDA.
One final thought, would FDA take an enforcement action against a foreign facility in the absence of having its own FDA investigators gather the evidentiary basis for this enforcement action? This is indeed a brave new world.
We will continue to keep you posted on all developments in this regard.