It’s been a difficult week for the nation as COVID-19 cases continue to grow in numerous states. Hospitalizations are increasing and some states are reaching capacity. We hope you are safe. Please be careful and continue your vigilance in maintaining your safety protocols.
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1.EUA vs FDA Authorization
Last week Lilly received emergency use authorization from the FDA for its antibody treatment. Though this drug has not shown benefit for hospitalized patients, there is some evidence that it may prevent complications in those who receive it earlier in their course. The evidence for the drug’s effectiveness is small leading some to question the FDA process of emergency authorization.
It is important to remember that emergency use authorization is not the same as traditional FDA approval. When a drug manufacturer applies for standard FDA approval they are required to submit evidence for the medication’s safety and its effectiveness. The FDA then performs a review of the provided evidence to determine if the necessary safety and efficacy standard is met. Approval for use in the U.S. is then given and the medication may be advertised for that purpose. Physicians are allowed to use medications for reasons other than the approved conditions, but manufacturers are not allowed to advertise these “off label” uses.
Emergency Use Authorization (EUA) is a new entity to the general public. Due to the pandemic and the need for rapid development of treatments, this category of applications has become more popular. This authorization allows a manufacturer to distribute a medication for the treatment of “chemical, biological, radiological, or nuclear (CBRN) threats, or emerging infectious diseases”. These medications do not require the volume of evidence for safety and effectiveness to be presented for this approval. The relevant U.S. code states: “FDA Commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN threat agents when there are no adequate, approved, and available alternatives.”
The distinction between these two applications is important. One is a formal “approval” with evidence showing safety and efficacy, and another is “authorization” for use in the absence of any known treatment in order to combat an emerging threat. Many of our current COVID-19 treatments are experimental and being utilized under EUA. This improves the timeline of a drug or product’s availability to the public, but does not carry the same “approval” as a standard medication.
2.Cases Increasing In New York City and State
Total cases continue to increase in the State of New York and in New York City. As of today the state is reporting an overall case positivity of 2.95% with focus zone areas reporting a 7 day average as high as 10%. In addition, NY City is reporting a 7 day average of 2.5%, thankfully dropping slightly away from the 3% bar set by the Mayor for school and business closure. Unfortunately, death rates are also increasing. With the holidays quickly approaching, this is an especially troublesome trend. Many have plans to travel and be with family, and we know that travel increases exposure. We also know that groups of people congregating indoors increases exposure risk. This will be a significant test of our ability to maintain our mitigation protocols at home and at school – distancing, mask use, quarantine. States and institutions have already put into place “test out” strategies for persons in quarantine. To date there has been only one published study awaiting peer review- a mathematical model from Yale – supporting the practice of testing to end quarantine early. Caution is needed before adopting such strategies until there is more evidence. With mounting pressure to allow travel, decrease quarantine, and remove restrictions for the upcoming holidays, the current trend in cases and hospitalizations nationwide serves as a warning.
3.A School Outbreak Story
Last week one of our member schools experienced a COVID-19 outbreak… or so we thought. It began with two students being sent home after screening positive for symptoms at school. Both students were encouraged to be tested after leaving and their parents complied. Each took their child to be examined and received a rapid COVID-19 tests which resulted positive. When student 1 tested positive, the classroom was closed and everyone exposed was asked to begin quarantine for exposure, and to be tested. When student 2 also tested positive, the school cast a wider net and tested all teachers as well. One teacher tested positive, but this teacher had no interaction with the two students who tested positive. The teacher was new, had no symptoms and noted that she had tested negative the week prior before starting this new position. After multiple discussions, we were faced with a decision. Do we close the school? Do we test everyone? All this came in a flood of information in less than 24 hours.
Though the outbreak seemed to signal a bigger problem in the school, some unusual things began to surface. After our discussions, the teacher in question reached out to her primary care physician for retesting on the same day of her positive rapid test. Another rapid test was performed by her physician, which was negative, and this time a confirmatory PCR test was sent. In addition, student 1 had a confirmatory PCR test performed. Both of these PCR tests were negative, and each was conducted on the same day as the rapid test which was positive. What does this mean?
In our prior newsletters, we discussed the limitations of rapid testing, especially in people who are asymptomatic. The FDA has also published a letter to healthcare providers about the false positive results that may occur with rapid tests. Could this “outbreak” in the school be a series of false positives? Two of our cases could definitively be labeled as false positives, the teacher and student 1, since both received more reliable PCR testing on the same day as their rapid tests. In combination with the lack of symptoms, a negative PCR is sufficient to exclude COVID even when a rapid antigen test is falsely positive. At this point, student 2 was encouraged to also obtain a PCR test. This was performed 2 days later and returned negative. However, since this PCR test was not performed on the same day as the rapid test, student 2 could not definitively be determined to have not been infected. It was theoretically possible for the student to be positive on day 1 and then negative on day 3 after recovering, meaning isolation for this student was necessary. It also meant a 14 day quarantine for this classroom.
Ultimately, this series of false positive rapid tests resulted in the temporary closure of two classrooms, the mass testing of all teachers, significant confusion over test results, and the quarantine of one classroom. The case highlights several important points:
- If your local department of health is not available or unwilling to consult with you (as in this case), it is important to have a reliable resource to help you navigate this confusing landscape. We were happy to fill this role for this school.
- Rapid testing has limitations. The false positives cause significant interruption to schools and may result in necessary isolation and quarantine, or even school closure. It is important to keep in mind these limitations when sending people for testing. PCR testing remains the best standard we have for determining COVID-19 infection.
- Screening should be done daily, and any symptom should prompt isolation of the student and a recommendation for testing or a physician note stating the symptoms are due to another illness.
- When confusion arises around test results, the assumption is that the results are true. This requires rapid isolation of those who test positive and closure of classrooms in order to begin quarantine of everyone exposed. Though mask uses is the best protection we have against the spread of covid, it does not preclude someone from quarantine after exposure.
4. When is it ok to end isolation?
When a person tests positive for COVID-19, they are asked to isolate for 10 days. However, isolation doesn’t end simply because 10 days have passed. The CDC also recommends:
- 10 days since symptoms first appeared and
- 24 hours with no fever without the use of fever-reducing medications and
- Other symptoms of COVID-19 are improving*
*Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation
The criteria for symptom improvement and absence of fever are important. A recent publication in the American Journal of Preventative Medicine examined 137 people discharged form the hospital after recovery from COVID-19 and found that 16% had positive tests after two weeks. The two symptoms that correlated most with persistent positive results were sore-throat and rhinitis (nasal congestion and runny nose). However, there have been other studies documenting persistent positive results. The CDC states the following about people who test persistently positive:
” Available data indicate that persons with mild to moderate COVID-19 remain infectious no longer than 10 days after symptom onset. Persons with more severe to critical illness or severe immunocompromise likely remain infectious no longer than 20 days after symptom onset. Recovered persons can continue to shed detectable SARS-CoV-2 RNA in upper respiratory specimens for up to 3 months after illness onset, albeit at concentrations considerably lower than during illness, in ranges where replication-competent virus has not been reliably recovered and infectiousness is unlikely. The etiology of this persistently detectable SARS-CoV-2 RNA has yet to be determined. Studies have not found evidence that clinically recovered persons with persistence of viral RNA have transmitted SARS-CoV-2 to others. These findings strengthen the justification for relying on a symptom based, rather than test-based strategy for ending isolation of these patients, so that persons who are by current evidence no longer infectious are not kept unnecessarily isolated and excluded from work or other responsibilities.”
So, for the majority of people who are symptom free by 10 days, isolation can be ended and repeat testing is unnecessary. However, making sure that symptoms are gone (with the exception of tase and smell loss) is important as some may be infectious up to 20 days.
5.Vaccines … are they really being rushed?
As we grow closer to the release of multiple vaccines, many are wondering how manufacturers have been able to produce vaccines in such a short time. Historically, this process has taken years or decades. Does this mean we can not trust these newer vaccines? No, but a better understanding of the vaccine development process and how it has changed for COVID-19 will shed light on this question.
- Research Funding: Initial research and development of potential vaccines is costly. It requires a significant investment on behalf of pharmaceutical companies with no guarantee of success. For this reason, potential methods of vaccine development must “prove” their methods of development and efficacy through significant research before receiving costly funding for further study and production. This obstacle was overcome by the large amount of money invested by the U.S. government and other countries in advance of a known vaccine. Governments invested heavily in multiple companies with multiple varieties of vaccines in the hope that most would prove successful.
- Production time: Pharmaceutical companies shoulder the burden of financial risk until a final product is proven to be safe and effective. In the case of COVID-19, the worldwide pandemic coupled with the investment from numerous countries removed much of that burden. Pharmaceutical companies were able to begin mass production of vaccines doses while completing the final phases of their human trials. This allows drug deployment to occur as soon as government approval is obtained.
- Prevalence: The large numbers of cases worldwide helps manufacturers in phase 3 trials. Once a potential vaccine is administered to a group of volunteers, they must be exposed to the disease to prove the vaccine is protective. If the disease is rare and exposure rates are low, this process may take years. However, in the case of COVID-19, exposure is not an issue. The increasing numbers of cases actually helps this process by increasing exposure of volunteers. This allows completion of the phase in a much shorter time frame.
- Disease characteristics: COVID-19 is not selective in its infection. All ages, genders, and races are susceptible to infection. This is also beneficial for manufacturers since the pool of test subjects is not isolated to a small group. For example, a vaccine for a disease that only effects middle aged women of indigenous American descent would be far more difficult to study and then test in a pool of volunteers. The fact that COVID-19 effects such a wide section of humanity makes the development of a test pool of volunteers easier.
These are only a few of the many ways that a worldwide pandemic allows for more rapid development of a vaccine. There have certainly been advances in technology that allow manufacturers to create vaccines on a “platform” or structure that can be used for multiple diseases by replacing small pieces relevant to the specific disease. This is similar to “plug and play” use of technology where a standard communication process is created for multiple devices to interact with each other. The improvement in vaccine creation has played a significant role in the vaccines we see nearing completion of study.
To date, both Pfizer and Moderna have announced success of their vaccines. This is good news but the process of vaccine approval has yet to be started. Announcements from the manufacturers are promising. However, the complete trial information from both companies must be provided to the FDA as part of the approval process, and then released to the medical community at large for review. These steps are anxiously awaited by physicians worldwide.
6.Immunity and COVID-19
There was much discussion early in the pandemic surrounding the duration of immunity after a person has recovered from COVID-19. Multiple studies showed that antibody levels dropped quickly after infection and might be undetectable as soon as 3 months after infection. Though this was a source of much media attention, it is actually a normal response to infection by the human body. There are other parts of the immune system charged with “remembering” the infection and causing an immune response when the body sees the virus again. These B and T cells, remain in the body and increase antibody production again when needed. A new study yet to be peer reviewed, suggests that these B and T cells remain detectable for more than 6 months. The values seen in the study were similar to other diseases where vaccines offer immunity for decades. This is welcome news of the possibility of very long immunity after vaccination or infection.
Thank you for being a subscriber. As cases increase, we are here to support you in your efforts to keep your schools and businesses safe. Please don’t hesitate to reach out when COVID makes its way into your community.