After initially receiving negative feedback on its proposal to implement a quality metrics reporting program, the FDA’s proposed 2016 program could represent an effective means to getting around travel restrictions imposed by COVID-19.
By Aaron Badida, JD
Background and Context
The FDA regulates and inspects thousands of manufacturing, distribution, storage and dispensing facilities. While the agency is supposed to inspect facilities every two years, it can be difficult for it to do so due to resource constraints and their physical locations outside of the US.
The result is that the FDA often discovers systematic quality issues after they’ve been occurring for a while. One potential solution to this problem would be to require companies to report data on the quality of their facilities to the FDA, which could then be used by regulators to determine which facilities are potentially experiencing an active problem, and therefore require immediate inspection.
The FDA was given the statutory authority to do this in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA). Section 706 of the law gave the FDA the authority to inspect certain records, including manufacturing quality metrics. The ability to collect real-time data and quality metrics would in theory allow the FDA to better allocate on-site inspection resources, while also providing the tools to enhance surveillance of offshore manufacturers.
FDA used this authority to develop its proposed Quality Metrics Reporting Program (QMRP). According to the FDA, this program was designed to meet the following goals:
- to help develop compliance and inspection policies and practices, such as risk-based inspection scheduling of drug manufacturers;
- to improve the Agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and
- to encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing.
Among the key challenges for this program would be the development of meaningful metrics that could be standardized, reported, interpreted and acted upon by FDA officials. That challenge would prove more difficult than initially anticipated.
The FDA has made two attempts to provide guidance that would lay the groundwork for the implementation of the QMRP. The first attempt was in a July 2015 Guidance, in which FDA proposed requesting drug quality metrics from a drug manufacturer in lieu of an inspection. This was initially proposed as a mandatory FDA policy change, rather than a voluntary policy. However, industry countered that such requirements would need to be enacted through regulation—not guidance. Industry also raised concerns that many of the proposed metrics were overly broad.
In response to industry pushback, the FDA published a subsequent guidance in November 2016 that framed the quality metrics reporting as voluntary for a limited time. Specifically, the FDA revised the language to provide for a “voluntary phase of the quality metrics reporting program” under which the FDA would not “take enforcement action based on errors in a quality metrics data submission” for data submitted in good faith.
Neither guidance was ever finalized, however, and the FDA has not provided any guidance on its next steps—if any—for the QMRP.
Despite the legal impediments to the implementation of the QMRP as proposed, the FDA has provided insights into what types of metrics it plans to incorporate to achieve these goals. The proposed metrics included:
- Lot Acceptance Rate (LAR), which shows how effectively the manufacturing process is working.
- Product Quality Complaint Rate (PQCR), which gives insights into end user feedback
- Invalidated Out-of-Specification (OOS) Rare (IOOSR), which helps provide insights into lab quality.
Ideally, metrics requested under this program would be proxy measurements for FDA inspections. Industry feedback on the November guidance offered a sense of how manufacturers felt about the initial approach. Overall industry sentiment is that LAR, PQCR and IOOSR are difficult to acquire and would provide little insight into actual issues related to quality manufacturing.
Trade associations and developers expressed concern that the burden of routinely providing such metrics would outweigh any potential benefit—even if it meant being able to avoid for-cause or routine inspections.
For example, BIO reiterated its belief that the guidance needs to be regulation, and that the complexity of the system and requirements will demand iterative versions of quality metrics reporting. The group also had concerns about the confidentiality of data submitted under this program. Going a step further, PhRMA recommended a comprehensive redesign of the QMRP that could occur collaboratively between agency and industry.
While the reaction to the 2015 and 2016 quality guidance documents were broadly unfavorable, COVID-19 may have created an ideal scenario to revisit the idea of using quality metrics to avoid in-person inspections where possible. For pharmaceutical and biopharmaceutical companies, the proposal may now be significantly more palatable.
The challenges of the global pandemic have put many routine inspections on hold. The FDA has had to find new ways to maintain its responsibility to ensure quality and safety while ensuring finite resources are adequately put in place to address COVID-19. Safety concerns about onsite inspections also remain top of mind, as the FDA seeks to avoid domestic travel and practice social distancing.
A recent AgencyIQ analysis of FDA site inspections found that FDA inspections reached the lowest amount in a decade in March 2020, indicating that few inspections are taking place.
Since the epidemic began, the FDA has indicated that it’s making use of “alternative approaches” of inspecting facilities as it works around complications with travel and obtaining visas for its workers. FDA spokesperson Jeremy Kahn told AgencyIQ:
“During this interim period, we are utilizing additional tools and approaches to ensure the quality of products imported into the U.S. which have proved effective in the past. Specific examples of our alternative approaches include denying entry into the U.S. for unsafe and inferior quality products, physical examinations of products arriving at our borders or product sampling and testing prior to release into commerce, reviewing the compliance histories of facilities, using information shared by trusted foreign regulatory partners through mutual recognition and confidentiality agreements, and requesting records directly from firms “in advance of or in lieu of” on-site inspections.
That last part—“requesting records directly from firms ‘in advance of or in lieu of’ on-site inspections”—is derived directly from Section 706 of FDASIA, indicating that the agency may already be exercising similar authority as part of its “additional tools and approaches.”
The public health emergency created by COVID-19 may create an opportunity to test the FDA’s QMRP approach. Given the needs of industry and the FDA, COVID-19’s creation of inspection backlogs, manufacturing site shutdowns or lockdowns and long-term uncertainty could make QMRP a mutually agreeable solution, especially for companies hoping to gain further market access.
Where industry comments initially expressed that the benefit of the guidance was not worth the administrative lift, a reassessment may be in order.
If the FDA does endeavor to revive or revise the QMRP, it will have to take care to address the legal concerns around the initial guidance. In order for the requirements of the program to be mandatory and carry the force of law, the FDA may pursue rulemaking, as requested by industry advocacy groups. However, the lengthy notice-and-comment process may not be ideal currently. The development of guidance for a useful QMRP might take a while, unless FDA pursues a direct final rule using emergency authority.
A more likely outcome is that the FDA would pursue a voluntary approach, in which it creates incentives to engage in reporting. For instance, the FDA could allow companies to take certain actions only with quality metrics reporting for the duration of the public health emergency that it might not allow otherwise.
To date, there has been no indication about how the FDA plans to leverage QMRP requirements and records inspection authority during COVID-19.
Even with QMRP and limited onsite inspection, however, the FDA could still face issues with data fraud. In the past, some companies have been found to use “secret” books where real data are kept, while data given to regulators are kept on a separate set of books only after the products are re-tested to acceptable levels. For example, in 2014, the FDA banned Indian pharmaceutical manufacturer Ranbaxy from marketing drugs in the US after it was discovered that the company intentionally reported false drug quality information to the FDA.
Still, a metrics-driven “inspection” approach might punish companies that have enacted high standards for quality, while rewarding those that established ones that are significantly more lax. Not ever unaccepted lot is evidence of low quality performance, but could in fact be evidence of a quality team that is operating out of an abundance of caution. And without fully-automated reporting systems, it could be operationally challenging to put together the metrics and calculate them.
For an effective quality reporting system in the long-run, the FDA will have to address a wide latitude of concerns, and it may benefit from taking the collaborative development approach suggesting by groups like PhRMA. Now more than ever, there may be more will from industry to find a solution and determine useful metrics that have the overall effect of maintaining quality and streamlining processes.