We have not yet posted on the COVID-19 pandemic, despite it being the greatest healthcare and global economic shock in recent history. Rocky Mountain Brain & Spine Institute blogs have tried to focus on neurosurgical topics, and while other coronaviruses have affected the central nervous system, COVID-19 is primarily a respiratory illness. We will leave the online discussions of the disease, its respiratory symptoms, and its specific treatment to the appropriate specialists.
However, in recent days the media has discussed the FDA, CDC and government processes in testing and medication/vaccine development. The question of, “why is this taking so long”, reverberates, and the FDA, CDC and our government officials have taken the brunt of the criticism. Similar queries and scrutinization have faced our field of neuroscience in quickly advancing the treatment of stroke, spinal cord injury, tumors or even spine degenerative diseases. Therefore it’s reasonable for a neurosurgery-directed blog to briefly address the processes and limitations of disease treatment in 2020.
First of all for some definitions, “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) is the virus causing the disease named, “coronavirus disease” (COVID-19).
TESTING
Tests for a disease process are typically created by scientists in the academic or private sector. This is commonly benchwork research that can broadly be applied in laboratory science, which the medical community can piggyback off of when appropriate.
What is the normal process for making a medical test or using it to detect disease?
It can take years or decades to create a new “test” for a new disease. It would seem simple and intuitive, but it can be difficult to determine what to even look for or to know what’s being testing. For example, when scientists thought to sequence the human genome in 1990, their goal was just to make a map of normal genes and study inherited traits. At the same time in the completely separate oncology realm, cancer treatment haphazardly focused on killing any rapidly replicating cell. But once the Human Genome Project completed in 2003, these two communities merged. Now that a normal reference genome had been sequenced, the chromosomic genesis of cancer became apparent and both molecular diagnosis of and gene-targeted therapies were subsequently developed. It’s been 17 years since genomic sequencing in cancer has been available, yet in 2020 scientists still don’t know how to completely use the test to diagnose cancer early when it potentially could most effectively be treated.
Similarly, polymerase chain reaction (PCR) was conceived in 1985 by a biotechnologist trying to analyze changes in DNA when he serendipitously developed a way to amplify DNA (the building blocks of genes). In 2020 PCR is now a gold standard for detecting viruses. Luckily, in the case of coronavirus, there have been 3 prior versions so we didn’t need to completely “reinvent the wheel” for the current pandemic. However, to detect the specific RNA in SARS-CoV-2, the test needs to know the genetics of the viral protein. The CDC obtained the viral sequence on January 9th. Of note, the very first known coronavirus patient started feeling sick in Wuhan on December 10th. So while the first cancer genome sequence appeared in 2006, three years after the completion of the Human Genome Project, scientists sequenced coronavirus in just 30 days. By January 22nd, commercial developers formulated a test, just one day after the US reported its first case. That’s pretty quick.
Some have highlighted that the US may not have enough tests for everyone and the tests are not readily accessible. This may overly simplify the test. Even though a PCR test can be “simple” to create once the viral gene sequence is known, they’re complicated to execute. It takes a dedicated lab… even home ancestry kits take about 6-8 weeks to tell the red-haired and freckled guy he’s from Ireland. A lab technician must carefully mix a patient sample with tiny portions of chemicals in tiny tubes, of which any contamination can ruin the test. Even in a skilled academic lab with multiple machines and numerous techs, about 2,000 tests can be performed per day. (The US population is 327 million people). There are not many academic labs in every state, and there are other viruses besides SARS-CoV-2 that are afflicting Americans these days. At the University of Washington, for example, their labs have increased staff from around 50 to 90 people, now operating 7 days a week and 24 hours a day. They’ve highlighted one medical scientist in the media, who during the first weekend after the FDA authorization, worked until two in the morning, went home and slept three hours, and came back to the lab. Can anyone predict how scientifically accurate our labs are going to be when we have technicians testing for coronavirus on 3 hours of sleep?
We may know the outcome of such scenarios. Other countries around the world are testing more patients per day than the US. For example, South Korea has tested over 250,000 people. However, their tests had a ~47% false-positive rate. What that means is that this test was wrong 47% of the time it said the patient had coronavirus. Would you be happy if US doctors diagnosed you with coronavirus, but in reality, it was a coin flip whether they were right? This is the inverse relationship between pace and accuracy.
In the end, even in 2020, it takes about 6 months to develop an accurate PCR to test for a virus that can confidently tell when someone has the disease. That test takes time to perform by specialized technicians. Science is never conducted as a popularity contest but instead advances through testable, reproducible, and falsifiable theories (Michio Kaku). And realistically, they say that medicine is an art… not a science. Did Michelangelo paint the Sistine Chapel ceiling overnight? Nope
MEDICATIONS AND VACCINATIONS
Click to enlarge photo
Formulating a medication or vaccine is somewhat regulated by the Food and Drug Administration (FDA).
What is the normal process for approving a medication or vaccine?
It takes at least 10 years for a new medicine to complete the journey from initial discovery to the US marketplace. The average cost to research and develop each successful drug is about $2.6 billion for the company.
If a company seeks FDA approval, the drug must complete a 5-step process:
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Discovery/ concept – Company develops a drug that may treat a condition
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Preclinical research- Company performs laboratory and animal tests to discover how it works and whether it could be safe and work in humans- takes a few weeks to a year
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Clinical research
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Safety tests in humans- several months involving ~20-100 healthy volunteers
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Efficacy tests in humans- months to years involving several hundred patients split into treatment and placebo-controlled groups
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Randomized/ blinded tests proving a treatment benefit, dosing, and adverse effects- several years involving thousands of patients
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FDA review- After the company submits the application, the FDA reviews over about 2 years
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FDA post-market safety monitoring.
Accelerated approval exists as well. In 2012, Congress passed the Food and Drug Administration Safety Innovations Act to approve drugs quickly for serious conditions. Instead of assessing a standard endpoint, like whether a cancer drug can extend patient survival, an intermediate clinical endpoint can be used, like whether the drug shrinks the tumor a little. This process still takes months to years.
The FDA doesn’t actually test the drug itself before approving, so this is why they continue to monitor drugs post-approval to verify they’re legit. Contrary to what most people think, even FDA-approved drugs are not necessarily safe. Manufacturers recall about 4,500 FDA-approved drugs annually, due to problems not recognized.
Litigation then has a chance to insert itself in the US pharmaceutical market. Companies often study a drug for one or a few indications. The FDA may then approve the drug, just for those indications. However, the expectation may be for physicians to more widely use the drug “off label”. Litigation in the US costs these companies billions of dollars when the drugs are used “off label” or have unexpected adverse side effects. Most people consider this a “check and balance” on pharmaceutical companies. There may be some truth to that, however, it is these unanticipated costs in manufacturing drugs that lead not only to high drug costs but rigorous and time-consuming testing. Some have argued for why the US isn’t more like other countries in the pharmaceutical industry? One glaring answer is litigation. Other countries do not sue like Americans. It will be interesting to follow any litigation regarding chloroquine in the future, which is being discussed as a potential treatment option. Chloroquine is usually an anti-malarial medication. (Malaria is not a virus, like SARS-CoV-2). Thus far, chloroquine is being studied in Petri dishes. Are you a cell in a Petri dish? Chloroquine is not approved by the FDA for COVID-19 coronavirus. In fact, there are no FDA- approved therapeutics or drugs to treat, cure or prevent COVID-19.
There is a theory that drugs make it to market quicker in the European Union compared to the US. (The EU has its European Medicines Agency- EMA, and the US as its FDA). In actuality, pharmaceutical development progresses similarly in the EU to the US. Additionally, studies have shown that FDA review times are a bit quicker than the EMA. (FDA takes about 303 days and the EMA takes about 366 days). In looking at some recent drugs that were brought to market in both the US and EU, about 63% were brought to market first in the US and were available about 90 days sooner. Comparing first-to market times between the US and Canada, 85.7% of drugs were available first in the US and on average 355 days sooner. The big difference may lie in what actually is being approved by the FDA versus EMA? In the US, a drug or device needs to not only be safe, but efficacious. In Europe, they simply need to be safe.
Vaccines tend to be more difficult to make than other medications. Medication tends to treat a relatively unchanging disease. A vaccine needs to address a virus that mutates (changes) very quickly. Luckily with the swine flu (N1H1) in 2009, scientists already knew how to make a vaccine since it was an influenza variant. This is a large reason why N1H1 was seemingly less devastating. With coronavirus, it is a less understood virus, so the vaccine needs to be developed from scratch. By the time a vaccine goes through the process of FDA approval listed above, the SARS-CoV-2 may have already mutated and the vaccine becomes obsolete. Of course, no one wants to discuss the profitability of medicine, but companies make little money in developing a vaccine as compared to other medications.
Regarding vaccination in the United States, let’s also not forget the growing resistance to vaccination for known diseases. The Centers for Disease Control and Prevention found that the vaccination rates for measles, mumps, and rubella (MMR) in kindergartners in the 2017-2018 school year slipped nationally to 94.3%, the third year in a row it dropped. So while nearly 100% of our nation is screaming for COVID-19 vaccination, we know that over 6% of those people won’t even get their kids an MMR vaccine.
OTHER OPTIONS?
As it turns out, just like with general healthcare in the US, there are other potentially better and quicker options, besides relying on science or the government, to prevent or limit disease. Quarantine could be the most effective tool of avoiding disease (of course this doesn’t help those already infected). Contracting the virus may allow some of us to slow the spread.
A virus is an “obligate intracellular parasite”… it is not its own living organism, like a bacteria or fungus. For a virus, which is just a protein, to survive, it must be passed to other living things, so that it can glean nutrition off its host. If there are no other living things around, it simply dies off. A person CANNOT get coronavirus unless they acquire it from someone/something else. The degree of transmission varies with viruses. One difference between Ebola and coronavirus, for example, is that 2014 West African Ebola was far less transmissible compared to the current coronavirus, which is a large reason why Ebola never became a global reaction.
Some of us are misinterpreting the data on quarantine, possibly based on the reports from China, where COVID-19 reportedly originated in Wuhan. We know that a lock-down state was implemented on January 23, 2020. Nevertheless, the number of reported cases subsequently increased faster than ever. Why? Well, it’s not because quarantine did not work… it’s because of the incubation period. Lock-down occurred after a bunch of people already acquired the virus but did not yet show symptoms. Since quarantine in Wuhan and surrounding provinces, there has been an increase in new symptoms (previously infected before quarantine), yet a sharp decrease in new cases (novel infections after quarantine).
Quarantine has been around since the 14th century. During the epidemic in Italy spanning 1347-1352, the plague was spread by sailors, rats, and cargo between Sicily and the eastern Mediterranean. Basic medicine of the time period was completely impotent against the plague, so the only way to escape infection was to avoid contact with infected people or contaminated objects. 40 days was chosen as the length of isolation time needed to avoid contamination (possibly based on Jesus taking 40 days to cross the desert), so the term “quarantine” comes from “quaranta”… meaning 40 in Italian. Italy survived the plague. 18th-century Cholera and 20th-century influenza both were also halted by quarantine.
Regarding adherence to quarantine, the US may be poor. We’ve heard governors in California and Illinois already reprimand their people for not heeding the warnings to limit social contact. Our governments are now in some places mandating quarantine, which theoretically could help limit virus spread. However the US is already facing legal threats in response (It should be noted, it’s not technically the federal government’s authority to quarantine, but the 2,684 state and local public health department’s jurisdiction). In the US, quarantine may be the most extreme use of government power over people who have not committed any crime. Legally, the SCOTUS granted unlimited power for the government to quarantine us since ~1827, in the case Gibbons v Ogden. 1905, Jacobson v Massachusetts, verified, “Upon the principle of self-defense, of paramount necessity, a community has the right to protect itself against an epidemic of disease which threatens the safety of its members”. However, our Constitution prohibits both federal and state governments from denying anyone, “life, liberty, or property, without due process of law”. Quarantine historically has primarily limited the entrance to our country or crossing between states, and rarely involved confining traffic within a community. In our litigious US, there is some legal chaos erupting by citizens who do not want to be quarantined. The government is already facing numerous legal challenges in implementing self-isolation and mandated quarantine.
Quarantine is not the only option however. Social distancing can occur without overt quarantine. It’s difficult to know the optimal distance for separation, but there is data to suggest the staying indoors may disseminate viruses quicker than being en plein air. During the Spanish flu outbreak of 1918, there were “open-air” hospitals which reduced deaths amongst some patients and staff by fresh air, sunlight, scrupulous standards of hygiene, and reusable face masks. The concept of open-air medicine has been known since the 1700s in England as a way to treat children with tuberculosis, another pulmonary disease. Ultraviolet light inactivates influenza and other pathogens. Natural ventilation prevents the spread of disease. Sunlight improves depression.Wearing masks in public may be associated with a lower incidence of infection, however no controlled large studies have been undertaken to assess their effectiveness. N-95 masks are most effective, and cotton homemade masks may provide little benefit.
Of course, we should also remember that once some of us contract the virus, for which many of us may not suffer any symptoms, we will develop our own immunity to that strain. This virus seems to be more dangerous than the common flu, or viruses like Chickenpox (varicella), for which we used to have Chickenpox parties… It should be remembered that as early as 430 BC, survivors of smallpox were called upon to nurse the afflicted because they were inoculated. The concept of vaccination was brought to England by aristocrat Lady Mary Wortley Montague in the 1700s who observed variolation at the Ottoman court in Turkey. She watched the healthy squeeze pus from smallpox pustules into their own cuts to create immunity. Therefore it may be some consolation that the virus spread within the US should diminish as we become self-immunized.
CONCLUSION
Maybe if we all understand the safety measures and time it requires to accurately test for the disease and formulate new medications/ vaccines, rely less on the government, and take a little more responsibility on ourselves, we can limit the spread of the COVID-19 disease and become supportive of the experts.
Unfortunately, it sometimes seems the US is a country focused on blame… someone needs to be responsible. Often, science and medicine just don’t work that way.
