RAPS Regulatory Focus reported last Friday that the US Food and Drug Administration (FDA) released draft guidance on July 22nd that formalizes its plans for using remote regulatory assessments (RRAs) for FDA-regulated products to supplement onsite inspections as we work our way out of pandemic protocols and codify “new-normal” modes of operation.  

The 17-page draft guidance is in question-and-answer format and covers important topics regarding RRAs such as who would be subject to an RRA, whether RRAs are replacing other established means of obtaining information outside of inspections, whether the RRA counts as an inspection, and expectations regarding RRAs such as how the FDA requests them and what consequences medical device manufacturers face if they decline participation. 

Further, the draft guidance replaces guidance issued in April of last year in the height of the pandemic, Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.  The new guidance was published in the Federal Register on July 22nd and is currently in its 60-day period for industry comment and the Agency has requested additional authorities to expand the ability to use remote regulatory tools across all commodities as part its FY2023 budget request.

The new proposed guidance “lays out how we intend to leverage this tool [RRAs] to advance our mission as we further incorporate modernized approaches to protecting public health” said FDA Commissioner Robert Califf and Judith McMeekin, associate commissioner for regulatory affairs, explaining how the remote regulatory assessment tools were not intended to replace onsite inspections, but rather to work in conjunction with them.

This mirrors language that we heard last month at the annual Drug Information Association (DIA) meeting, which we reported on HERE.

The FDA may be easing from its pandemic response mode, but, like any industry and nearly every organization, two years of pandemic have normalized remote work for the agency and forced improvement in remote inspections.  The FDA announced during the annual Drug Information Association (DIA) meeting on June 22nd that they do not plan to return to pre-pandemic practices, but will instead be adopting a hybrid inspection model moving forward, combining a mix of record requests, remote interactive evaluations (RIEs) with onsite inspections, if deemed necessary.

“These will be tools, in my opinion, that we’ll continue to adapt to use. We will adapt the hybrid model or other models that will still help us. We’ll do a records request, and we’ll have an inspector in the facility for a focused [inspection]…or we will do a remote interactive evaluation to get an initial assessment to decide if we need to send someone over.” – Alonza Cruse, director of FDA pharmaceutical quality operations

With the announcement of this draft guidance, the Agency leadership said that these remote tools have “been a valuable tool in the nation’s response to the public health emergency, as we’ve fast-tracked their wide use to help get critical medical products to the front lines in the fight against the pandemic while keeping normal business operations moving.”  At this point, the Agency understands the benefits and challenges well as they’ve conducted over 1,470 domestic and 600 foreign inspections using remote methods over the past two years when the pandemic was at its height and travel restrictions made normal inspection methods impossible.

Just as most of our respondents from our 2021 Quality Digest study on the effectiveness of remote audits noted positive aspects of remote auditing that had the potential for collecting even better evidence in some situations than could be collected by traditional means, the Agency’s demeaner is likewise positive and the benefits of utilizing remote technologies are articulated in the draft guidance.

In response to the Coronavirus Disease 2019 (COVID-19) pandemic, FDA adapted its operations for field activities to provide oversight of regulated industry while mitigating the spread of COVID-19. One set of tools used during the pandemic for oversight of FDA-regulated products has been remote regulatory assessments (RRAs), as further described in this guidance. The term “RRA” (as defined in the Question and Answers section) is used to describe a category of activities for which FDA may use different terminologies, but that are all considered to be types of RRAs, including “remote interactive evaluations,” and “remote record reviews.”  Such activities, along with others identified in this guidance, are considered RRAs for purposes of this guidance. In the presence of travel restrictions during the COVID-19 pandemic, FDA utilized certain types of RRAs to assess establishments and their compliance with applicable FDA requirements. Based on this experience, FDA has noted the value of RRAs and concluded that they should be used for certain scenarios outside the current pandemic and for all types of FDA-regulated products.

FDA’s experiences so far have identified significant benefits in using RRAs. For instance, RRAs have assisted FDA in verifying corrective actions taken in response to inspections of previously compliant manufacturers and in gaining compliance insight when it was not practicable to inspect. RRAs have also provided information about deficient practices, which led FDA to take regulatory actions, conduct inspections, and have informed future inspection planning. RRAs have been used to help support, and reduce delays of, approval or authorization of marketing submissions for FDA-regulated products during the COVID-19 pandemic. In the food program, they have assisted in determining compliance with veterinary feed directive regulations, assessing foreign manufacturing process records, adding foreign firms to import alerts, and with issuance of warning letters.

Based on these experiences, FDA has determined that RRAs are valuable and, under certain circumstances, will continue to assist FDA during and beyond the COVID-19 pandemic, in its mission to protect public health, oversee regulated industry, and ensure all types of regulated products comply with FDA requirements.

Further, The FDA articulated several bullet-pointed benefits in the Q & A section of the document:

• Allowing FDA to remotely evaluate compliance of FDA-regulated products, clinical studies, and establishments, as appropriate. This may identify issues that lead establishments to promptly make corrective actions, which may enhance the establishment’s preparedness for their next FDA inspection.
• Having an RRA precede an inspection under section 704(a)(1) of the FD&C Act could reduce resource expenditure by (1) potentially reducing the time FDA is present at the establishment, and (2) helping optimize FDA’s time on-site, by reducing the extent of records to be reviewed during the inspection.
• FDA can make regulatory decisions, including the approval of an application or authorization for emergency use, without an inspection, when appropriate conditions are fulfilled, such as, the ability to verify information in the marketing submission. In such cases, the application approval, or the authorization, must still meet applicable standards.
• Providing FDA additional information to incorporate into a risk-based inspection schedule, thereby helping FDA use inspectional resources more efficiently and effectively.
• Assisting FDA in verifying corrective actions taken in response to inspections of previously compliant manufacturers.
• Helping to support, and reduce delays of, approval or authorization of marketing submissions for FDA-regulated products.

The guidance also acknowledges some of the challenges with conducting these types or remote activities, primarily citing technology issues such as good, high-bandwidth connections needed for live video streaming, as many respondents noted in the Quality Digest article last year.  After optimistically noting the ways in which remote audits might actually produce better evidence, we concluded:

To make remote audits truly effective, it’s clear that there are still some gaps to fill. Because it appears that remote auditing is here to stay, we owe it to ourselves to understand the gaps and start working toward solutions. I believe that remote auditing does have the potential to be as effective, if not more effective, than the exclusively on-site audits of yesteryear.

There are still some technological hurdles that need to be overcome to ensure connectivity throughout the location being audited. But perhaps more important, we need to invest in training our auditors to audit more effectively in remote scenarios.

The guidance states:

The technological expectations will vary depending on the type of RRA and its scope. Certain RRAs involve records requests, and the records may be submitted electronically or through other means. Other RRAs may require additional technological capability. For example, if FDA expects that the RRA could include the use of live streaming video, FDA may inquire about hardware or internet connectivity to assess IT operability, security, and privacy controls to protect the confidentiality of the data. The quality of the remote connection (e.g., connectivity, image quality, cameras used) should be adequate for FDA to review, observe, examine, and evaluate the requested records, documents, and other information (including electronic systems). To the extent practicable, technologies employed also should allow access for remotely viewing and evaluating operations at the establishment, as appropriate (e.g., aseptic practices, equipment cleaning and set up, material weighing and dispensing, instrument set up, sampling, and testing).

If an establishment is unable to support streaming video or other live virtual interactions, or if FDA determines that the streaming video or any other virtual interaction during the RRA does not permit a sufficient examination of the establishment or of a corrective action, FDA may use other available tools or may terminate the RRA and consider other actions necessary to exercise our oversight responsibilities of that establishment, such as an inspection.

The FDA plans to leverage a risk-based approach to determine whether to initiate an RRA. Such risk factors may include the location of the firm, its inspection history, complexity of the product and process, and travel restrictions.

While the draft guidance does state that an RRA may be initiated when The FDA cannot conduct an inspection due to travel limitation brought on by ‘pandemics, natural disasters, or other unstable situations making travel infeasible,’ it is important to note that the guidance also says that RRAs will not be used during or as part of an FDA inspection of an establishment and that RRAs and inspections will not happen simultaneously – i.e. FDA staff conducting an RRA remotely while other FDA staff are onsite conducting an inspection.

[An] RRA could precede, prompt, or be a follow-up to, an inspection. When an RRA precedes an inspection, FDA will generally conclude the RRA prior to initiating the inspection. FDA may combine any information gained from the RRA with any resulting observations from the subsequent inspection. In such circumstance, FDA would confirm any observations from the RRA during the inspection before including them on the Form FDA 483 Inspectional Observations.

Upon completion of an RRA, FDA may have a meeting with the establishment’s management to present a written list of RRA observations, but “[the] written list of observations will not be considered a final Agency action or decision…evidence collected…may be used in support of any such action or decision.”  FDA will not issue a Form FDA 483, Inspectional Observations, following an RRA.

The draft guidance does articulate that there are not punitive consequences for a firm declining participation in voluntary RRAs that were requested by The FDA, but it may cause delays in the firm’s applications for product approval, clearance, or authorization as the FDA ‘may not be able to conduct timely assessment of the establishment’s activities due to insufficient information,’ or it may necessitate an inspection to follow up on previous observations in which they might otherwise be able to gain sufficient evidence without inspection through the RRA process.  In the instance of a firm declining to participate in a mandatory RRA, it is noted that the firm will be in violation of the FD&C Act and that the FDA will then have to take appropriate action against products or establishments that are in violation.

The new draft guidance is currently open for industry comment and can be downloaded here.