By Phil Crooker, Vice President - Technical, Parexel Regulatory Services
Recently, the FDA Commissioner (Dr. Stephen Hahn) and the Director for the Center for Drug Evaluation (CDER) (Dr. Janet Woodcock) remarked that the very recently created Coronavirus Treatment Accelerator Program (CTAP) has received nearly 1,000 submissions. FDA has now started to prioritize those proposals with some assistance from existing non-profit organizations and a newly created public-private partnership.
This could be a “tipping point” when the agency begins to shift from short-term crisis management to medium and longer-term planning for managing policies and the workload emerging from the crisis stage. As Thales of Miletus remarked – “the past is certain, the future obscure.” With that in mind, here are some thoughts and opinions about how the regulatory landscape could look over the next 18 months or more.
FDA is operating at its peak discretion as long as the public health declaration is in effect. How long will that last? There are news stories more frequently about 2021 being a realistic target for “normal.” And some reports of new models that show risk of another surge concomitant with the flu season in the fall. Once the public health emergency is rescinded the FDA loses significant reasons for the use of extreme discretion. Since the government will want to keep maximum flexibility in place, I’d expect that the public health emergency declaration will last until 2021. Other major health authorities with similar or analogous legal systems (EMA, PMDA, TGA, Health Canada) are likely in the same position and will need to continue their global cooperation on similar footings.
Regulatory applications following emergency use
Even if a firm has been granted an EUA from FDA or other emergency use status from another global health authority, the firm still has an obligation to continue to develop the products and to submit proper marketing or clearance applications. Health authorities will likely choose to review those quickly, since they have already seen some data and have been able to observe how the product or device has performed in the field. The list of those emergency use grants will diminish, and they will be placed into the market using applications where the health authority may have granted flexibility for content and used a much faster review process.
Regulatory applications for novel treatments
Proposals that come into the FDA CTAP, the EMA rapid response team or the PMDA COVID-19 hub will probably follow the same pattern as the applications following emergency use grants.
Discretion and flexibility
The pandemic didn’t eliminate the regulatory processes that existed before and health authorities will keep using those. The COVID-19 proposals are being funneled into those channels and health authorities using their discretion to modify data requirements and timelines. The IND/IMPD/CTX didn’t go away, and neither did GxP. In some cases, the legal standards for use are different – for emergency use of a product or device health authorities can rely on “likely to be effective” rather than demonstrating efficacy with different safety standards such as “more good than harm.” But those won’t be in place forever and there will be a return to the established standards. Health authorities will need to balance how they meet existing legal standards without compromising public health – there were already papers in the literature proposing that the FDA standard for approval had been shifted to a post-marketing burden.
Real World Evidence (RWE/RWD) could change how those standards are met. Health authorities will be under enormous pressure to use data collected in the field during the pandemic that more closely resembles RWE/RWD and use those data to approve products or devices either following emergency use grants or collected during a clinical trial or both. The endless discussion of “anecdotal data” to support HCQ + azithromycin rather than wait for “pragmatic” controlled clinical trial data is an example. Those “anecdotal” data may fall into the RWE/RWD bucket when all is said and done. The push to collect and use those data will gather more and more momentum when citizens and activists and lawmakers ask “why could you do that during a pandemic when massive numbers of people were at risk but you can’t do it for less riskier situations?” The challenges will be access to the data (there is a thicket of privacy laws that come into play, especially in the EU) and how will a health authority ensure that the data meet the indicia of data integrity that health authorities have used for other GxP and application data.
Specific guidance and policy that goes away
As the public health crisis winds down, the health authorities will need to evaluate which guidance documents and policies they will need to rescind. Things can get messy here. Government agencies run into trouble when they suddenly change course. It can be done but there are also prohibitions against applying those changes once a company has started down a certain road. For example, if a company has submitted a regulatory application and the public health emergency has been declared to be over, then the health authority should review the application against the standards and policies in place at the time the development programs were running. Same holds true for inspection standards.
Some policy may stay
Even if certain guidance documents can be retired after the pandemic emergency is over, some of the underlying policies may be hard to remove. They may not remain in use for COVID-19 but the framework and legacy will last. Think how the HIV/AIDS crisis eventually led to user fee programs and how those programs have evolved over 30 years. Compliance programs are ripe for use fee oversight and greater transparency for policies, procedures and interactions with health authorities. If remote audits and desk reviews are enough to protect public health in a crisis there will be pressure to keep those in place. Regulatory applications that are now considered “streamlined” could become the norm. Accelerated review times could become more common if the application content were more targeted. And there will be pressure from the public when they realize that health authorities can react quickly and will want some of that culture to stay in place.
Distributing the workload
Public/private partnerships are beginning to pop up. The NIH is running one that includes FDA, EMA, government agencies and private sector firms to help evaluate and prioritize treatments for COVID-19. The non-profit Reagan Udall Foundation has started a complete inventory of development programs for the public, with FDA participating and asking for their help. The UK has a program that coordinates research and development for treatments. These collaborations may eventually wind down the COVID-19 related work but I’d expect them to remain in place for other uses such as greater international collaboration and scientific assistance for novel treatments, technologies, orphan/rare diseases. These organizations could help FDA and other health authorities in developing guidance and assessing development programs. These could eventually reach the point of reducing the FDA workload and reviewing lower risk applications if the right legislation were in place.
Eyes around the world from a distance
Global cooperation was already underway. But now it will be essential to have greater reliance on cooperative agreements mutual
recognition agreements. International travel may be the last leg of the economy to recover and even then, it could take years to recover. Getting agency personnel on site around the world may not be practical or even permissible for some time. But local travel may be more available. Health authorities will need to increase their use of these agreements and be willing to act on them. When inspections resume, they will probably have a far greater domestic coverage than international component. Inspectors in the EU will need to get comfortable with reports from FDA and vice versa as a routine practice. FDA or EMA won’t have the luxury of looking at a report they didn’t write and then scheduling a new for-cause inspection to get their own staff on site. Existing policies will need to be re-written and new policies developed that account for identifying and managing risk from a distance. As a result, the desk-top or remote audit support will be the new norm for a few years and other health authorities will likely collaborate to develop more aligned approaches for inspection like what ICH did for application content and review.
Clean-up on aisle 6
As the pandemic winds down, the clean-up will start. This could take years. It will range from how to develop a new raft of SOP’s and workstreams to account for and justify GxP deviations, ensuring data integrity for what could be a mixed bag of sources and conditions for clinical use along with added complexity for manufacturing, converting emergency use grants to regulatory approvals, pushing applications through clinical development and marketing review with data that may have been collected before/during/after COVID-19, fortifying supply chains with site changes to more reliable locations to satisfy politicians, citizens and insurance underwriters, GxP inspections that will ramp up and the preparation companies will need to face what could be revised inspection techniques, the corrective actions that will come when companies face adverse results and the disputes companies will have with regulators.
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