Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Update on the Moderna Vaccine Candidate

Today Moderna issued another press release to update the information available on their vaccine candidate. The results are consistent with the previously released results and will be followed by a much more detailed release of information at an FDA advisory panel meeting, expected to be on December 17, 2020.

The new cases are more than double the 95 cases from the November 16 press release. The total is now 196 symptomatic cases – 185 in the placebo group and 11 in the mRNA-1273 group – efficacy of 94.1%. There were 30 severe cases, including 1 death, in the placebo group and no severe cases in the mRNA-1273 group.

We do not know how many asymptomatic cases are in either group, so this route of transmission by vaccinated people is still a possibility.

Another part of the press release raises different questions.

Efficacy was consistent across age, race and ethnicity, and gender demographics. The 196 COVID-19 cases included 33 older adults (ages 65+) and 42 participants identifying as being from diverse communities (including 29 Hispanic or LatinX, 6 Black or African Americans, 4 Asian Americans and 3 multiracial participants).

But . . .

The study includes more than 11,000 participants from communities of color, representing 37% of the study population, which is similar to the diversity of the U.S. at large.

The minority rate in the study is stated to match the 37% minority rate of America, but the symptomatic infection rate among American minorities in the study is 42 out of 196 (21.4%), but according to a meta-analysis of over 18 million patients in the Lancet, the symptomatic infection rate among minorities is significantly higher than 37%:

Patients from ethnic minority groups are disproportionately affected by Coronavirus disease (COVID-19). We performed a systematic review and meta-analysis to explore the relationship between ethnicity and clinical outcomes in COVID-19.

How is this study of randomized volunteers, who are allegedly representative of the American population, producing symptomatic infection rates that are much less than half of what is expected among minorities?

The November 18 Pfizer/BioNTech vaccine candidate press release only states:

Efficacy was consistent across age, gender, race and ethnicity demographics.

I did not find any details of the actual numbers in the press release, nor in any of the links. The Moderna press release has a similar statement, even though the numbers provided disagree with that statement: “Efficacy was consistent across age, race and ethnicity, and gender demographics.” Is the Pfizer/BioNTech statement more trustworthy, because it does not provide any numbers? No, but this is something that needs to be addressed for all of the vaccine candidates.

What are the Pfizer/BioNTech numbers for minorities? The FDA meeting for Pfizer/BioNTech is scheduled for December 10, so we should learn a lot more from that open to the public by video FDA meeting.

Why does the Moderna press release list such disproportionate numbers, but not mention that they are disproportionate? There is no reason to expect that a placebo would provide this kind of disproportionate protection.

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Why 90% vs. 62% for the Efficacy of the AstraZeneca Vaccine Candidate?

 

There was a press release from AstraZeneca at 7 AM today. It includes two different dosing methods with two dramatically different rates of efficacy. One group received half a dose, followed by a month later by a full dose. The other group received a full dose, followed by a month later by another full dose.

 

One dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). More data will continue to accumulate and additional analysis will be conducted, refining the efficacy reading and establishing the duration of protection.

 

Usually, the result of the differences in dosing is to use the lowest effective dose, in order to minimize any side effects, which are usually dose related. A higher dose is expected to be more effective, but also to have more side effects.

 

The part people are having a hard time explaining is that the 90% efficacy is in the smaller dose group. This does not seem to make medical sense, but this is what people who understand statistics expect.

 

Why?

 

Daniel Kahneman explains this in his excellent book, Thinking, Fast and Slow. He uses the following example as an introduction:

 

A study of the incidence of kidney cancer in the 3,141 counties of the United States reveals a remarkable pattern. The counties in which the incidence of kidney cancer is lowest are mostly rural, sparsely populated, and located in traditionally Republican states in the Midwest, the South, and the West. What do you make of this?

 

This is known informally as the Law of Small Numbers. Intuitively, we can come up with many different explanations about a healthy rural lifestyle, or something else. Kahneman follows that with the statistics on counties with the highest incidence of kidney cancer, which are also mostly rural, sparsely populated, and located in traditionally Republican states in the Midwest, the South, and the West.

 

The important factor is not lifestyle, not politics, and not geography. The important factor is that these are all sparsely populated counties, which means that the number of cases of kidney cancer will be disproportionately affected by the addition/subtraction of a tiny number of cases.

 

The small sample size is the most likely explanation for the 90% efficacy in the half dose, then full dose group. When more cases of COVID-19 are diagnosed among those who have received the half dose, then the full dose, expect the estimate of benefit to drop closer to 70%. The 70% efficacy is also based on small numbers, but those numbers (including the 90% sample) are more than four times the size of the 90% sample. This is not certain. This is statistical probability. A reasonable person should feel comfortable in placing a wager on the results dropping to near 70%.

 

In other words, the news is worse than expected, although still good news. There is another vaccine candidate that, based on the preliminary numbers, meets the approval criteria of better than 50% efficacy.

 

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What Do the Moderna Vaccine Candidate Press Releases Tell Us?


 

I had thought that the vaccine studies would only be recruiting people up to 55 years old, which was the age limit on the phase 1 studies, but there is significant representation of people over 65 and people with serious comorbidities. This is excellent news.

 

According to one press release from Moderna:

The COVE study includes more than 7,000 Americans over the age of 65. It also includes more than 5,000 Americans who are under the age of 65 but have high-risk chronic diseases that put them at increased risk of severe COVID-19, such as diabetes, severe obesity and cardiac disease.

 

The other important concern I had was the need to store the vaccine at around -80 degrees C, which would limit access for a lot of people, even in America. From another press release, dated 4 minutes earlier, Moderna:

today announced new data showing that mRNA-1273, its COVID-19 vaccine candidate, remains stable at 2° to 8°C (36° to 46°F), the temperature of a standard home or medical refrigerator, for 30 days. Stability testing supports this extension from an earlier estimate of 7 days. mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days and at room temperature for up to 12 hours.

 

There is an excellent analysis of the press release on preliminary efficacy results at STAT News, which has been ahead of the rest of the media in recognizing the serious nature of this pandemic.

 

It is important to remember that a press release, even about something this serious, is a commercial, intended to promote the company’s product. The information provided by Moderna in the press releases has not been peer reviewed. The numbers may change as mistakes are caught and conclusions are examined. That is OK, because there will be thorough analysis of the results before any vaccine candidate is approved for use outside of these experiments.

 

How will we know when a vaccine is safe and effective? I provided my criteria in August, when I wrote about a vaccine approved by President Putin, based on inadequate research:

I want to see recommendation of a vaccine by the people who know the most about vaccines – Paul Offit, Michael Osterholm, Peter Hotez, and Anthony Fauci. They need to be able to see all of the evidence. The only reasonable conclusion about a refusal to share the evidence with any of them is that there is something bad being hidden. These are not politicians. None of these medical experts have shown signs of being influenced by political pressure.

 

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2020 ACLS Repeats the Mistakes of 2015 ACLS

 

 

The International Liaison Committee on Resuscitation (ILCOR) has updated the ACLS (Advanced Cardiac Life Support) recommendations by making excuses for the evidence.

 

We have been using epinephrine for 50 years without evidence of improved outcomes that matter to patients.

 

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest (Paramedic2) shows that epinephrine does not improve outcomes for prehospital patients.

 

In conclusion, in this randomized trial involving patients with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of survival at 30 days than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.

 

Rather than limit treatments to those with high quality evidence that they improve outcomes that matter to patients, the recommendation is to keep giving epinephrine, because eventually someone might provide something – anything – to support epinephrine.

 

What about amiodarone?

 

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest (ALPS) showed that amiodarone also does not improve outcomes.

 

Conclusions Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

 

If amiodarone was mentioned, I missed it. Both epinephrine and amiodarone had large placebo-controlled research results released showing that the outcomes are worse with epinephrine and worse with amiodarone.

 

There is still no evidence that any ventilation produces better outcomes than compression-only resuscitation, but it looks like the intervention will continue to be recommended.

 

In the absence of evidence of benefit, inadequately tested interventions should be avoided.

 

The goal is to protect the patients, not to protect the interventions.

 

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What Treatments Will the Anti-Science President Use?

Now that President Trump’s attempts to prevent himself from developing COVID-19 have failed, for the president and for many of those around him, will the president continue to reject science, when it comes to treatment?

President Trump promoted hydroxychloroquine[1], [2], [3], which is a useful treatment for several medical conditions, but not effective against COVID-19. Should President Trump expose himself to the side effects, when there is no expectation of any benefit?

A reasonable person would not take hydroxychloroquine. A superstitious person might. This is a version of Pascal’s wager.[4] You have everything to gain, but nothing to lose. Except that Pascal’s wager ignores the more probable harms that comes from the preferred choice and assumes that all harm comes from not making the preferred choice. Therefore, Pascal’s wager is actually, You have everything to lose, but only a ridiculously long shot at any gain. Being unreasonable, Pascal’s is a losing wager.

President Trump promoted oleandrin[5], which is not a useful treatment for anything, unless you are trying for suicide or murder. Should President Trump take poison, when there is no expectation of any benefit? I suspect that many of the people who have been harmed by President Trump would say, Yes, but that is not the way medicine works.

The role of medicine is to provide the most effective treatment, taking into consideration the potential harm, in order to improve the outcome for the patient. Killing people, other than as part of medically assisted suicide (where the goal is to end the suffering of the patient at the request of the patient), is for other professions.

President Trump promoted convalescent plasma[6], which is only supported by low quality evidence and no completed high quality research. Maybe convalescent plasma works, but we may not know for a long time, because the high quality research will have trouble continuing. The EUA (Emergency Use Authorization) makes convalescent plasma available to patients outside of controlled research.

Since doctors have trouble understanding science, how do we expect patients to understand?

I was involved in a discussion with one experienced emergency physician who claimed that he should be able to give hydroxychloroquine to patients outside of controlled trials, because he would be giving hope. I asked how this is any different from what alternative medicine does? He responded just as an alternative medicine promoter would – with logical fallacies about What if . . . ? We should actually hope for better from doctors, who are supposed to understand medicine. This willful ignorance is probably the most deadly medicine doctors prescribe.

Will President Trump be as smart as British Prime Minister Boris Johnson and leave the science to the scientists? President Trump has not provided any evidence to expect reasonable decisions, yet.

What does work? If given early, remdesivir might be effective.[7] On the other hand, remdesivir might not be that effective.[8] If oxygen is used to treat low oxygen saturation, dexamethasone[9], [10] is the most effective treatment.

If you want to minimize your chances of having to make these choices, wear a mask and eye protection, stay physically away from other people, and wash your hands.

Footnotes:

Some of the footnotes are to what I have previously written about these treatments. They contain links to the research on the proposed treatments, rather than add footnotes for all of links to research and other evidence.

[1] Hydroxychloroquine – The More You Know, The Worse It Looks

Rogue Medic

May 22, 2020

Article

[2] What’s the Good News on Hydroxychloroquine?

Rogue Medic

June 6, 2020

Article

[3] Is Hydroxychloroquine Effective Against COVID-19?

Rogue Medic

July 31, 2020

Article

[4] Pascal’s wager

Wikipedia

Article

Criticism of Pascal’s Wager began in his own day, and came from both atheists, who questioned the “benefits” of a deity whose “realm” is beyond reason, and the religiously orthodox, who primarily took issue with the wager’s deistic and agnostic language. It is criticized for not proving God’s existence, the encouragement of false belief, and the problem of which religion and which God should be worshipped.[4][15]

[5] The Oleandrin Scam Exposes Incompetent Doctors

Rogue Medic

August 23, 2020

Article

[6] Is convalescent plasma safe and effective? We answer the major questions about the Covid-19 treatment

STAT

Lev Facher

August 23, 2020

Article

[7] Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Christoph D Spinner 1, Robert L Gottlieb 2, Gerard J Criner 3, José Ramón Arribas López 4, Anna Maria Cattelan 5, Alex Soriano Viladomiu 6, Onyema Ogbuagu 7, Prashant Malhotra 8, Kathleen M Mullane 9, Antonella Castagna 10, Louis Yi Ann Chai 11, Meta Roestenberg 12, Owen Tak Yin Tsang 13, Enos Bernasconi 14, Paul Le Turnier 15, Shan-Chwen Chang 16, Devi SenGupta 17, Robert H Hyland 17, Anu O Osinusi 17, Huyen Cao 17, Christiana Blair 17, Hongyuan Wang 17, Anuj Gaggar 17, Diana M Brainard 17, Mark J McPhail 18, Sanjay Bhagani 19, Mi Young Ahn 20, Arun J Sanyal 21, Gregory Huhn 22, Francisco M Marty 23, GS-US-540-5774 Investigators

JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349.

PMID: 32821939 PMCID: PMC7442954 DOI: 10.1001/jama.2020.16349

Free Full Text from JAMA

[8] Remdesivir and COVID-19

The Lancet

October 3, 2020 (Yes, that is tomorrow’s date.)

DOI: https://doi.org/10.1016/S0140-6736(20)32021-3

Article

[9] Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report

RECOVERY Collaborative Group; Peter Horby 1, Wei Shen Lim 1, Jonathan R Emberson 1, Marion Mafham 1, Jennifer L Bell 1, Louise Linsell 1, Natalie Staplin 1, Christopher Brightling 1, Andrew Ustianowski 1, Einas Elmahi 1, Benjamin Prudon 1, Christopher Green 1, Timothy Felton 1, David Chadwick 1, Kanchan Rege 1, Christopher Fegan 1, Lucy C Chappell 1, Saul N Faust 1, Thomas Jaki 1, Katie Jeffery 1, Alan Montgomery 1, Kathryn Rowan 1, Edmund Juszczak 1, J Kenneth Baillie 1, Richard Haynes 1, Martin J Landray 1

July 17, 2020

N Engl J Med. 2020 Jul 17; NEJMoa2021436. doi: 10.1056/NEJMoa2021436. Online ahead of print.

PMID: 32678530 PMCID: PMC7383595 DOI: 10.1056/NEJMoa2021436

Free Full Text from NEJM

[10] The RECOVERY Trial: Dexamethasone for COVID-19?

REBEL EM

June 23, 2020

Article

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Mask vs. Vaccine – Which is More Effective?

Currently, mask vs. vaccine is an easy answer. Masks are 100% more effective than something that is not available. Eventually, mask plus vaccine may be the best answer.

According to the evidence, the the masks decrease the amount of virus that is able to be detected on the other side of the mask, regardless of whether the mask is being worn by an infectious person trying to avoid infecting others or the mask is being worn by a healthy person trying to avoid becoming infected.

The dose of virus does seem to matter in transmission of disease.

This does not mean that vaccines will not help, assuming that a safe and effective vaccine is eventually available. The stated cut off level to be applied for approval of a vaccine is currently at least 50% effective. Masks are already more than 50% effective.

“I might even go so far as to say that this face mask is more guaranteed to protect me against COVID than when I take a COVID vaccine, because the immunogenicity may be 70%,” Redfield said in testimony before a Senate appropriations committee. “And if I don’t get an immune response, the vaccine is not going to protect me. This face mask will.”[1]

That statement was later contradicted by President Trump, but that statement was not contradicted by any credible scientist and was not contradicted by any credible physician. Oddly, the article title suggests that Dr. Redfield walked back his statement, although the article never states that. This may be because the headline is often not written by the person writing the article, but by an editor, looking to get more clicks.

Masks work.

Vaccines are not available and probably will not be available until sometime next year.

If we want the economy to recover, we need to be aggressive about wearing masks to protect others and to protect ourselves.

This is from a paper written in 2009 about influenza, which is transmitted the same way SARS-CoV 2 is transmitted. These were people with influenza, wearing masks, and coughing. The results with an N95 mask and a surgical mask show that both decreased the amount of virus, that would be spread by a cough, to the undetectable level.[2]

Masks do not protect your eyes, so you should consider wearing eye protection. Masks also do not protect your hands, so wash your hands. Typhoid Mary might not have killed anyone if she had washed her hands.

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Footnotes:

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[1] CDC Chief Walks Back Masks v. Vaccine Comments
By Ralph Ellis
WebMD
Article

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[2] A Quantitative Assessment of the Efficacy of Surgical and N95 Masks to Filter Influenza Virus in Patients with Acute Influenza Infection
D. F. Johnson, J. D. Druce, C. Birch, M. L. Grayson
Clinical Infectious Diseases, Volume 49, Issue 2, 15 July 2009, Pages 275–277, 
https://doi.org/10.1086/600041 Published: 15 July 2009

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The Oleandrin Scam Exposes Incompetent Doctors

President Trump has made another medical recommendation. This one is more dangerous than the last. As long as a lot of physicians are willing to harm patients in order to promote their political agenda, President Trump is willing to keep playing doctor and providing them with ways to harm patients. We can hope that the FDA (Food and Drug Administration) takes action to protect patients from such doctors.

Hydroxychloroquine was supported by low-quality research, but some physicians couldn’t wait to promoted it. That is alternative medicine – the opposite of competent medicine.

When high-quality evidence on the use of hydroxychloroquine in humans with COVID-19 was published, these physicians insisted that the research was politically motivated, each time a new high-quality study was published. That is the argument used by alternative medicine, not real medicine. Every high-quality study shows that there is no benefit from hydroxychloroquine for COVID-19 patients. The risks are greater than the potential benefits. Competent and ethical physicians should limit the use of hydroxychloroquine to well-controlled research.

Now we have a more extreme danger to patients from alternative medicine and promoted by President Trump. Oleandrin is an extract of the oleander plant and is not supported by any research in humans. The only research supporting oleandrin as a COVID-19 treatment is in test tubes, which means that this is not even as well tested as the vaccine approved by President Putin earlier this month. If there is any use in humans, it would be in a Phase 1 trial. Not even that level of research has been done, yet.

The obvious image to use to explain this is from xkcd.

The mouse over text states: Now, if it selectively kills cancer cells in a petri dish, you can be sure it’s at least a great breakthrough for everyone suffering from petri dish cancer.

Oleandrin, and thousands millions of other chemicals, kill coronaviruses in petri dishes. Killing cells in petri dishes does nothing to help patients.

For more detailed information read this article or this article or listen to this podcast.

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What Does the Approval of a Russian Vaccine Mean?



Today, after testing on a grand total of 76 people, President Putin announced the approval of a vaccine in Russia, Sputnik-V, to prevent COVID-19.

We knew another pandemic was coming, because we understand evolution. We should have been prepared. We were prepared under the Bush administration. We were prepared under the Obama administration. The current administration chose to stop wasting money on being prepared.

There are three human phases of testing generally required before the approval of a vaccine or drug, after testing in other animals. Phase I is testing in humans for common adverse effects, dosing ranges, and to generally learn how the body reacts. For the most discussed vaccine trial, Moderna had 45 people (three groups of 15 people each receiving different doses of vaccine) in their Phase I trial.

Phase II expands the use to people who are not as healthy as the people in Phase I and to a more people. Phase III is refining this, based on the results of the earlier trials. Phase I and II are being combined in some vaccine trials. Phase II and II are being combined in others.

The Moderna Phase III trial of mRNA-1273 (mRNA is messenger RiboNucleic Acid – the stock ticker for Moderna, Inc. is also MRNA) is expected to enroll 30,000 people who have no evidence of previous COVID-19 infection.[1] Half will get mRNA-1273 and half will get a meningitis vaccine as a placeboish control. While a placebo often means inert, a saline solution injection would not produce the temporary fever, soreness, and/or redness to the site at the same rate as an actual vaccine. This is expected to keep the volunteers from being able to tell which they have received and it provides a benefit to those in the placebo group.

Russia has enrolled 76 people in Phase I and President Putin has announced that Phase III will happen at the same time as the mass vaccination of the people most likely to be exposed to infection. This is Phase IV – post approval study.

Russia has not announced any challenge testing, which might have been a more ethical approach than skipping Phase III. Challenge testing has not being announced anywhere for COVID-19 vaccine testing, because of the ethical concerns. With an expected 1/2% to 1% fatality rate, a much higher rate of serious complications, and an unknown rate of long term complications that appear to be related to COVID-19, it is difficult to justify intentionally exposing people to infection with a vaccine of unknown ability to protect the people being exposed. Thousands of people dying each day, thousands more developing serious complications each day, and thousands more developing long term complications each day. Where is the line drawn between approving challenge testing and not approving it? Where is the line drawn between challenge testing and skipping Phase III trials?

When will the Russian vaccine be given to people? Some time in October.

What could go wrong?

Meanwhile the Moscow-based Association of Clinical Trials Organizations (Acto), which represents the world’s top drug companies in Russia, urged the health ministry to postpone approval until after phase-three trials.

Acto executive director Svetlana Zavidova told the Russian MedPortal site that a decision on mass vaccination had been carried out after a combined first- and second-phase tests on 76 people, and that it was impossible to confirm the efficacy of a drug on this basis.[2]

Will this be just another political intervention, like hydroxychloroquine? Only time will tell.

What would indicate that the United States has a safe and effective vaccine?

I want to see recommendation of a vaccine by the people who know the most about vaccines – Paul Offit, Michael Osterholm, Peter Hotez, and Anthony Fauci. They need to be able to see all of the evidence. The only reasonable conclusion about a refusal to share the evidence with any of them is that there is something bad being hidden. These are not politicians. None of these medical experts have shown signs of being influenced by political pressure.

The pandemic was not at all a surprise. The conspiracy theorists will misrepresent this video, because of their lack of understanding of what they are hearing. If it doesn’t support their prejudices, they don’t seem to hear anything at all, as if they have been programmed to ignore valid evidence and logic.

Pandemic Preparedness in the Next Administration: Keynote Address by Anthony S. Fauci – Feb. 14, 2017 – Almost 3 years before COVID-19, but the medically competent audience understood that this was a reasonable prediction to make in 2017. If you don’t understand that, watch the whole video.



Every reasonable person should have known there would be another pandemic, but we have media that discourage understanding, especially about science.


Late addition – 10:55 – 8/12/2020 – For further information, Carl Zimmer has an article in The New York Times going into more detail. A couple of important quotes from the article are below.

‘This Is All Beyond Stupid.’ Experts Worry About Russia’s Rushed Vaccine
August 11, 2020
by Carl Zimmer. Andrew Kramer and Katherine J. Wu contributed reporting.
The New York Times
Article

“This is all beyond stupid,” said John Moore, a virologist at Weill Cornell Medical College in New York City. “Putin doesn’t have a vaccine, he’s just making a political statement.”

Dr. Nicole Lurie, a former assistant secretary for preparedness and response at the U.S. Department of Health and Human Services and currently an adviser at the Coalition for Epidemic Preparedness Innovations, said the lesson that the U.S. government should draw from Mr. Putin’s announcement is clear.

“This is exactly the situation that Americans expect our government to avoid,” she said.

Footnotes:

[1] Phase 3 clinical trial of investigational vaccine for COVID-19 begins – Multi-site trial to test candidate developed by Moderna and NIH.
Monday, July 27, 2020
NIH (National Institutes of Health)
News Release

[2] Coronavirus: Putin says vaccine has been approved for use
Analysis by Fergus Walsh, Medical correspondent
BBC
Article

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