· FDA wants to set standards for COVID-19-related viral pneumonia treatment processes
· Real-world evidence for the COVID-19 vaccine: Understanding bias and tracking abilities will be key
· WHO publishes vaccine guidance containing standards for emergency use
· CDER data offers first glimpse at the impact of its compounding enforcement discretion policy on COVID-19 drugs
Welcome to our COVID Weekly Recap, AgencyIQ’s weekly wrap-up of the top regulatory developments related to COVID-19. The following analysis was available to AgencyIQ subscribers earlier this week as part of our daily regulatory intelligence briefings. Contact us to find out how you can become a subscriber to AgencyIQ to receive this analysis (and much, much more) each day.
FDA wants to set standards for COVID-19-related viral pneumonia treatment processes
By Laura DiAngelo, MPH
September 21, 2020
With limited information currently available about COVID-19’s natural history, the FDA indicated today that it is looking at how to measure lung damage related to viral pneumonia for COVID-19 patients.
- COVID-19-related viral pneumonia is “rapidly progressive and often fatal,” leading to the death of 2-8% of individuals with the virus according to research on virus published in the medical journal Nature. If symptomatic, a patient may escalate from Severe Acute Respiratory Syndrome to viral pneumonia to acute respiratory distress syndrome (ARDS).
- “Computed tomography (CT),” or computerized imaging, “could shed light on several stages of disease detection and evolution,” according to the research in Nature—especially as challenges with diagnostic testing for COVID-19 remains. New research has been able to identify preliminary findings on the presentation of COVID-19 using CT, although “the use of chest CT scan as a primary tool for screening of patients under investigation for COVID-19 is fraught with significant issues.” These include general iatrogenic concerns, such as exposure to potentially infectious patients, but also “methodology limitations,” including a standard for CT for a novel virus. Still, according to preliminary reports on the natural history of COVID-19, “distinguishing COVID-19 from other serious, treatable conditions” such as pneumonia or influenza “is essential.”
- The FDA is looking into it, according to a new notice published on September 18. The agency said it would purchase software updates from Siemens Medical Solutions for its diagnostic ultrasound system. With the new software, the FDA says it will work “to develop tools and procedures for quantifying the percentage of lung covered by lung ultrasound (US) examinations, a new application heavily used to evaluate COVID-19 patients for extent of COVID-related viral pneumonia.” Once captured, the data will be turned into 3D volumes that will let the FDA evaluate the lungs.
- The natural history of COVID-19 is still not well understood—yet. For example, it’s not clear how long the after-effects of the virus last, although anecdotal reports indicate that there could be long-term damage to patients’ lungs and neurological systems. Advancing regulatory science to standardize processes could help developers and providers better understand how effective treatments are.
- What’s next? The notice is not a call for competitive bids, but rather a notice of intent to sole source. With the information gained through the better evaluations of infected lungs, both FDA and industry could increase their understanding of the novel coronavirus.
Real-world evidence for the COVID-19 vaccine: Understanding bias and tracking abilities will be key
By Laura DiAngelo, MPH
September 17-18, 2020
A two-day meeting held by the FDA to assess the potential role of real-world evidence (RWE) to support the development of vaccines, including those for COVID-19.
- Real-world evidence (RWE) is evidence about a regulated product’s safety or efficacy generated from real-world data (RWD). RWD is generally considered to be data captured outside of a traditional trial protocol—including data from insurance claims, registries and electronic health records (EHRs).
- The use of RWE to support preventive vaccines is an established practice, according to Jeff Roberts, Associate Director of Medical Countermeasures and Scientific Affairs at the FDA’s Center for Biologics Evaluation and Research (CBER). Specifically, RWE can be used to support vaccines when traditional clinical trials are unsafe or infeasible—such as in cases of emerging infectious diseases and when trying to understand safety and efficacy of vaccines in specific populations, like pregnant women or the elderly. There is some regulatory precedence for this, including with Merck’s Zostavax and Sanofi Pasteur’s Fluzone High Dose.
- Observational bias and confounding factors arelikely to be a challenge for using RWE to track the safety and efficacy of a COVID-19 vaccine. The populations slated to get any vaccine first, including first responders, health care workers and populations in congregate care settings, are also those most likely to have already been exposed to or infected with the novel coronavirus, explained the UK Public Health Agency’s Nick Andrews. In addition, health seeking behavior is likely to be a significant confounding variable. Vaccine hesitancy in the US has been increasing steadily in recent years, and understanding who seeks out a vaccine and who refuses vaccinations will be key to understanding the population of any observational RWE COVID-19 vaccine study. Some individuals will also have received other vaccines (including the flu vaccine), which may further complicate tracking efforts.
- It’s also likely that there will be more than one vaccine. FDA officials, including CBER’s Senior Epidemiologist Hector Izurieta, highlighted the need for any marketed vaccine’s packaging to be equipped with a barcode, allowing the product to be tracked. However, this will require all sites of vaccine administration to be able to scan the barcode—include pharmacies, community sites (e.g., firehouses) and nursing homes. According to Izurieta, these bar codes “can only be a good instrument if the pharmacy can actually tell us which vaccine they administer.” However, a plan to operationalize such a system is not yet in place. “We are trying to put some pressure into guaranteeing that the… administration of the vaccine is linked to the vaccine and its manufacturer,” he said. Especially assuming that there will be multiple vaccines available, this is “absolutely essential.” However, while “there’s [been] active discussions within the FDA,” no such plan is definitely set at this time.
- “What I can say is that both of our agencies [FDA and CDC] are pushing as hard as possible” to have coding, including potentially barcodes for scanning, set up before a vaccine is distributed, said Verani. “We won’t be able to do these studies well if there isn’t appropriate coding,” or if all sites distributing vaccines don’t have the ability to code appropriately. “We are optimistic that the coding will be in place, but plans are not finalized yet,” she indicated.
- “We do not want to be re-creating the wheel in the era of ‘Warp Speed’” said CDC Epidemiologist Jennifer Verani, who is leading the COVID-19 Vaccine Efficacy Task Force. As a result, the Centers have planned multiple studies using unified platforms, when possible, with the FDA, CDC and VA “planning to coordinate” to harmonize research efforts. Current plans include test-negative design studies, ecological analyses and case-control method studies. Prospective cohorts, she noted, are resource intensive but likely necessary, as retrospective cohorts using electronic health records (EHRs), clinical or vaccine registries will be limited to only the variables already available within those databases.
- Post-market efficacy studies will face challenges related to limited understanding of the epidemiology of COVID-19, according to Verani and CBER Senior Epidemiologist Hector Izurieta. Working to leverage baseline criteria from what limited information is available will be key to creating a complete picture, but these analyses may not be broadly applicable. For example, according to Izurieta, CBER is planning to study the risks of vaccines causing enhanced disease in health care workers, whose baselines of severe infection are already known as a population, as well as in children.
- What’s next? CBER’s Office of Biostatistics and Epidemiology will soon be publishing a manuscript on the natural history of COVID-19 in the Medicare population, according to Associate Director Rich Forshee. Aligning efforts to reduce redundancies and increase chances for a successful system to track multiple vaccines out in the market will be paramount, according to regulators, but the details haven’t yet been hammered out. “Regulatory agencies will need to sit together and align” on a strategy, noted CBER Office of Vaccines Research and Review Director Marion Gruber.
WHO publishes vaccine guidance containing standards for emergency use
By Alexander Gaffney, MS, RAC
September 28, 2020
Late last week the World Health Organization (WHO) published a “points to consider” document detailing how manufacturers of COVID-19 vaccines can demonstrate the safety, efficacy and quality of their products in order to obtain Emergency Use Listing (EUL).
- Emergency Use Listing efficacy criteria: WHO’s document explains that “results from both final report and pre-specified interim reports are acceptable” to support EUL. The primary efficacy endpoint would need to be the same as that for a full prequalification (50%, with a confidence interval of above 30%). Follow-up of study subjects after three months would be required to determine the extent of the vaccine’s duration of protection.
- Safety considerations: WHO indicates that trials should track local and systemic adverse events for at least 7 days after each vaccination, and track unsolicited adverse events for at least 21-28 days after vaccination. Serious events should be tracked for at least 6 months, and longer safety monitoring may be needed.
- Follow up with participants should occur for at least a year (“and preferably longer”) and include an assessment of both safety and efficacy. It should also be blinded to reduce the chance of bias.
- The guideline also included extensive detail about normal prequalification, though many of the details are similar to those previously published by the FDAand ICRMA.
CDER data offers first glimpse at the impact of its compounding enforcement discretion policy on COVID-19 drugs
By Aaron Badida, JD
September 23, 2020
The Center for Drug Evaluation and Research (CDER) yesterday released data on “Cumulative 503B Reported Drugs used for hospitalized patients with COVID-19.” This dataset provides insights into which 503B compounding pharmacies are making use of the FDA’s temporary guidance that allows compounders to make drugs they are otherwise prohibited from making.
- Outsourcing Facilities, also known as 503B compounding pharmacies, produce large quantities of drug products. Unlike 503A pharmacies, these facilities are allowed to ship products across state lines and are also permitted to compound limited quantities of products before the receipt of an individual prescription (based on the facility’s expectation that it will receive those prescriptions). These facilities are exempt from labeling and approval requirements, but are required to register with the FDA annually, meet cGMP requirements under 21 CFR 210-211 and are subject to FDA inspections.
- Under normal circumstances, compounding pharmacies are limited in the activities they may conduct.These facilities are typically not allowed to essentially copy drugs for which there is an FDA-approved version on the market, nor may they compound a drug from bulk substances due to quality and safety concerns. There are exceptions to these rules if a substance appears on the FDA’s “Bulks List” or if the subject drug is in shortage.
- Drug shortages due to COVID-19 led the FDA to exercise enforcement discretion with a temporary policy. Under guidance issued in April 2020, compounding pharmacies are permitted to make drugs, even if they are essential copies or not on Bulks List. This discretion is part of the FDA’s efforts to respond to drug shortages caused by the COVID-19 pandemic.
- The data shows concentrated use. Only eight unique outsourcing facilities made use of this policy, with QuVa Pharma accounting for 68% of the production. QuVa is a Texas-based 503B outsourcing facility founded in 2015. The company advertises that it specializes in “sterile compounded, ready-to-administer injectable products.” Nephron Sterile and SCA Pharmaceuticals were the next largest producers at about 10% each.
- The enforcement discretion originally applied to 13 substances used to treat COVID-19. That list has since grown to 16 substances, but just three accounted for 66% of drugs compounded under this guidance: fentanyl citrate, hydromorphone hydrochloride and morphine sulfate. QuVa produced the most of each of them. These drugs are typically used as painkillers and sedatives and can be helpful in reducing coughing fits and intubation.
What we’re watching
The White House’s battle with the FDA over the agency’s plan to release a guidance document regarding the use of the Emergency Use Authorization pathway to authorize a vaccine for COVID-19. While the White House has reportedly asked for the FDA to justify the data it plans to ask for, AgencyIQ has another thought.
Unlike regulations, guidance doesn’t really give the FDA any additional authority. Rather, it just indicates to industry that the FDA plans to interpret existing regulations in a particular manner. While the White House may pressure the FDA to make changes, ultimately, the decision whether to authorize (or not authorize) a vaccine is the FDA’s—that is, unless HHS Secretary Alex Azar steps in to over-rule a decision not to approve an EUA.
“I have unwavering confidence and trust in FDA’s professional career staff to continue following the science and ensuring that science remains the driver of the agency’s regulatory decision-making in our fight against #COVID19 and beyond on behalf of public health. I am often asked about how and when FDA will authorize or approve a vaccine to protect against #COVID19. Here is my answer: when the agency’s scientific experts have completed their review and are ready to do so, and not a moment before.”
FDA Commissioner Stephen Hahn, who took to Twitter to praise FDA’s staff and make the case that it will be their call whether a vaccine is approved and at what time.
“There is concern that an EUA is a lower bar than the FDA’s rigorous standard for safety and effectiveness. Or that the EUA decision could be subject to political influence similar to some clumsy, recent intrusions into reports issued by the Centers for Disease Control and Prevention. We reject the claim that a vaccine EUA inherently falls short of FDA’s gold standard review, or that the process will be hijacked.”
Former FDA Commissioners Scott Gottlieb and Mark McClellan, writing in the Wall Street Journal about their trust in the FDA’s vaccine process. Their advice: The FDA should make vaccines available “in a careful and limited way, to those at highest risk of contracting infection and suffering a bad outcome.”