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Monday, April 5, 2021

Asian countries routinely give anti-COVID antivirals EARLY. They have 1/100th the fatalities of the West. That’s not a coincidence.

 Copyright 2021 Robert Clark



In these articles once again nowhere did they even ask the question what treatments are they using in these countries with the radically reduced fatality rates. These are doctors investigating this remember, doctors whose job is to treat people, and they never ask the question how do you treat your sick.


 The national treatment protocols for COVID of giving antivirals EARLY for some of the Asian countries go all the way back to last year to March. It’s stunning when you think about it but if the question had been asked of them of what treatment strategies do you use, the researchers would have gotten the answer over and over again, “We use antivirals EARLY”, “We use antivirals EARLY”, “We use antivirals EARLY”, “We use antivirals EARLY”. It would then have been apparent that EARLY treatment with antivirals is important for bringing the virus under control.


 This study also concludes countries using anti-malarials are much better at keeping the epidemic under control:


National Consumption of Antimalarial Drugs and COVID-19 Deaths Dynamics : an Ecological Study.
“COVID-19 (Coronavirus Disease-2019) is an international public health problem with a high rate of severe clinical cases. Several treatments are currently being tested worldwide. This paper focuses on anti-malarial drugs such as chloroquine or hydroxychloroquine, which have been currently reviewed by a systematic study as a good potential candidate and that has been reported as the most used treatment by a recent survey of physicians. We compare the dynamics of COVID-19 death rates in countries using anti-malaria drugs as a treatment from the start of the epidemic versus countries that do not, the day of the 3rd death and the following 10 days. We show that the first group have a much slower dynamic in death rates that the second group.”


 Some national treatment protocols in Asian countries advising EARLY treatment with antivirals:


In China:


Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition)

Page Views 浏览量: 145539 Updated 发布时间:2020-03-16 12:00:32


http://kjfy.meetingchina.org/msite/news/show/cn/3337.html


And:


Health 17:30, 26-May-2020

COVID-19 treatment: Antivirals, anti-inflammatory drugs, blood thinner and mechanical ventilation

Updated 22:28, 26-May-2020

Antiviral treatment 
Ranko Škrbić, dean of the Department of Pharmacology at University of Banja Luka, asked about the most effective antiviral therapy that has been used in the Chinese hospital against the coronavirus. 
Hou Xinguo, Deputy Director of Endocrinology Department at Qilu Hospital, said that several antiviral drugs including alpha-interferon, ribavirin and abidol have been recommended in the COVID-19 diagnosis and treatment guideline issued by China's health authorities. But based on their clinical experience, the antivirals could be useful on patients only at the early stage of infection, as they did not have significant effects on severely ill patients. 
He added that according to the guideline, no more than two antiviral drugs should be used in combination.
 

https://news.cgtn.com/news/2020-05-26/COVID-19-Frontline-Chinese-doctors-share-treatment-experience-QNHrqxKtNe/index.html


And:


Published online 2020 Oct 8. doi: 10.1080/20016689.2020.1818446

PMCID: PMC7580738

PMID: 33133431

Chinese guidelines related to novel coronavirus pneumonia

Tingting Qiu, Shuyao Liang, Monique Dabbous, Yitong Wang, Ru Han, and Mondher Toumi

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580738/


In South Korea:


Gov't recommends use of antiviral drugs for COVID-19 treatment

Published on Feb 13, 2020

'고령중증에 에이즈치료제 권장'…코로나19 치료원칙 나왔다

South Korea has unveiled a set of treatment guidelines for COVID-19.
It consists of administering an anti-HIV medication twice a day.
This is the nation's first treatment protocol for those who show severe symptoms.
Kim Jae-hee has our top story.
Infectious disease experts in South Korea have agreed to the use of antiviral drugs in the treatment of severe coronavirus cases, senior patients, and those with underlying diseases.
On the other hand, it was concluded that young patients, or those with mild symptoms, seemed to have improved after 10 days and without any antiviral treatment.
"Young and healthy people have mostly shown improvement without any special treatment. But older patients or those with underlying diseases are in need of the medication from an early stage."
Expert says differences in treatment depending on a patient's age is actually quite normal.
"Most viral infections tend to heal even without any treatment... thanks to our body's immune system. But old age in itself can raise risks,... and many senior patients have underlying diseases, so it's recommended that they undergo antiviral treatment."
The government's guidelines recommend Kaletra, an anti-retroviral medication used to treat AIDS for a duration of 7 to 10 days.
Chloroquine or Hydroxychloroquine, a medication used to prevent and treat Malaria can be used as an alternative.
But experts says, while the government's announcement may sound promising, it might not make much of a difference to current treatment metThere won't be a significant difference in the treatment methods. It's an antiviral drug that we are already using, and its effectiveness has not been fully proven. It's still just a recommendation."
But the expert is optimistic, saying that the recurrence rate of the novel coronavirus is low.
"It seems unlikely that a recovered patient will catch the virus again. In fact, there are very few reports of patients being re-infected when they've recovered from other coronavirus diseases such as SARS and MERS."
He added that all seven of the patients who have made full recoveries in South Korea had no serious underlying diseases, and are unlikely to be re-infected.

Kim Jae-hee, Arirang News.

#Wuhan #coronavirus #drugs 

Gov't recommends use of antiviral drugs for COVID-19 treatment




In Taiwan:


Interim Guidelines for Clinical Management of SARS-CoV-2 Infection 

(5th edition) 

Translation Editor-in-Chief Prof. Wang-Huei Sheng, M.D. PhD et al.

Affiliation Department of Medicine, National Taiwan University 

Ministry of Health and Welfare 

Taiwan Centers for Disease Control 

March 26th, 2020 


https://www.cdc.gov.tw/En/File/Get/_Dv_q75ZjLcNeRvlnrPgUg


In Hong Kong:


News > Medscape Medical News

Triple Antiviral Combo May Speed COVID-19 Recovery

Neil Osterweil

May 11, 2020

https://www.medscape.com/viewarticle/930336

(May need free registration.)


And:


South China Morning Post

Hong Kong public hospitals to revise Covid-19 treatment guidelines, highlight effective drugs behind low mortality rates.

Victor Ting

27 August 2020·3-min read

Hong Kong’s public hospitals will revise clinical treatment guidelines for Covid-19 patients to better highlight the effectiveness of an antiviral drug that has helped achieve one of the lowest coronavirus death rates in the world.
Dr Owen Tsang Tak-yin, medical director of the Hospital Authority’s infectious disease centre at Princess Margaret Hospital, made the revelation at a media briefing on Thursday as the city’s third wave of infections showed signs of easing, with health officials reporting 21 new cases, taking the local tally to 4,755, with 81 related deaths.
“The third wave has been very rapid and fierce,” Tsang said. “But despite that, we have one of the lowest mortality rates worldwide, at about 1.6 per cent.”
One factor that helped suppress the death rate was effective treatment, which centred on a cocktail therapy involving antiviral drug Interferon; Kaletra, a drug originally used for HIV/Aids, and Ribavirin, which was also used for hepatitis C, according to Tsang.
The treatment guidelines, which were last updated in June, would be revised “very soon”, Tsang said, and would highlight Interferon as the major medication for Covid-19, combined with Ribavirin. But Kaletra may lead to some side effects and has proved to be unsuitable for some patients, causing liver problems in such cases.
Another antiviral drug, Remdesivir, was found to be most effective among patients in severe condition requiring oxygen support, but less effective in those who are critically ill and requiring intubation, while Hydroxychloroquine and Chloroquine have been ruled out as overseas research have shown their ineffectiveness.

https://sg.news.yahoo.com/hong-kong-public-hospitals-revise-142129309.html


 It’s notable that Hong Kong decided against HCQ following Western studies. But those studies did not test it for EARLY treatment which is essential for antivirals. But no matter. COVID-19 is a virus easy to treat. Multiple antivirals are effective treating if given EARLY.


In Thailand:


Am J Trop Med Hyg. 2020 Jul; 103(1): 48–54.

Published online 2020 May 18. doi: 10.4269/ajtmh.20-0442

PMCID: PMC7356442

PMID: 32431287

Critical Care Management of Patients with COVID-19: Early Experience in Thailand

Ranistha Ratanarat,1,* Chaisith Sivakorn,2 Tanuwong Viarasilpa,1 and Marcus J. Schultz3,4,5

Antiviral treatment before ICU admission.
Thailand has set national guidelines for antiviral treatment. Patients with mild symptoms receive chloroquine or hydroxychloroquine plus a boosted protease inhibitor, lopinavir or darunavir plus ritonavir. Favipiravir is not recommended in mild cases because of its limited availability.8
Favipiravir is an antiviral RNA polymerase inhibitor for which most preclinical data are derived from its influenza and Ebola activity.16 It is given to all patients with proven COVID-19 who have symptoms or signs consistent with pneumonia, or when there is hypoxemia (SpO2 < 95% on room air).8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356442/


In Singapore:


Interim Treatment Guidelines for COVID-19 (Version 1.0, dated 2 April 2020) 

ABSTRACT Background In December 2019, pneumonia cases caused by a novel coronavirus occurred in Wuhan, Hubei Province. As of 11th February 2020, the World Health Organisation has officially named the disease “COVID-19”. In addition, virologists in the coronavirus study group have officially announced the name of the virus to be “SARS-CoV-2”. This guideline provides evidence-based recommendations on the therapeutic management of patients with COVID-19 in Singapore. 

https://www.ncid.sg/Health-Professionals/Diseases-and-Conditions/Documents/Treatment%20Guidelines%20for%20COVID-19%20%282%20Apr%202020%29%20-final.pdf



  Robert Clark

Tuesday, March 16, 2021

Vaccine companies keep hidden COVID-19 safety data for elderly patients. UPDATED: 4/11/2021

                                                 Copyright 2021 Robert Clark


UPDATE: 4/11/2021

 Normally, I put updates at the bottom of the original blog post but this is so important I'm putting it at the beginning.

 Public health agencies have focused on giving the COVID vaccine to elderly recipients, such as nursing home residents. It's surprising then that the safety info has not been released to the public specifically for elderly recipients. 

The Pfizer research report included the safety data for those over 55 and the Moderna report for those over 65. On that basis it was claimed the safety data has been provided for the elderly, say, those over 75 such as residents in nursing homes. But the safety issues for vaccines specifically for the elderly can be significantly different compared to those even in the range of 65 to 74:

Coronavirus Vaccine and Seniors: Could There Be a Problem?

The fact that elderly people do not respond well to immunizations has largely been ignored in most discussions of COVID-19 vaccines, despite this being the group in greatest need. Most of the scientific community’s experience with vaccine development for any disease has been focused on vaccinating the relatively young.


by Byram W. Bridle Shayan Sharif
July 24, 2020 Topic: Public Health Region: World Blog Brand: The Reboot Tags: Coronavirus COVID-19 Vaccines Senior Citizens Elderly
https://nationalinterest.org/blog/reboot/coronavirus-vaccine-and-seniors-could-there-be-problem-165360

 So the fatalities for those contracting flu among the elderly, ~75 yrs. and above, is 8 times higher than even those in the 65 to 74 yrs age range.

 Then a key issue is that the COVID vaccines cause flu-like reactions in a large percentage of people. From the vaccine trials we would estimate the number of all people who would get fevers after the second shot, the more injurious one, to be ~15%. But disturbingly data taking from actual vaccine recipients with the v-safe collection method put the number having fever after the second dose as ~30%:

COVID-19 vaccine safety update
Advisory Committee on Immunization Practices (ACIP)
March 1, 2021
Tom Shimabukuro, MD, MPH, MBA
CDC COVID-19 Vaccine Task Force
Vaccine Safety Team

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/28-03-01/05-covid-Shimabukuro.pdf

 Judging by the vaccine trials these fevers only last a day or so. However for about 1-2% of cases the fever can last over a week. That would be quite concerning for an elderly patient.

 And still note this data is still not telling us about the important case of elderly patients. Then I was still looking for some reports discussing the safety question of the vaccines for the elderly.

 Two recent articles looked at the COVID vaccine for elderly recipients:

Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination.

and:

Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers – a Danish cohort study

 They both concluded the effectiveness in the elderly after the 2nd shot is only ~60%. This is surprising since both the Pfizer and Moderna trial reports both implied that the effectiveness in the elderly approached the 90% range seen in younger recipients. But it is in keeping with the prior results that vaccines are not as protective for the elderly. 

 BUT these two recent report still did not consider the safety issues.

 Quite astonishingly there have been no reports that looked at the safety data for the COVID vaccine specifically for elderly recipients.
 
 A report that might allow us to make a comparison of the COVID vaccine recipients for serious medical conditions has recently come out:

 Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study.

 The title is rather misleading in that it does not give the number of adverse events for COVID vaccine recipients. It estimates instead the prevalence of conditions such as strokes, blood clots, and heart attacks in the general population. This is especially important to know given the recent reports of strokes in vaccine recipients in order to see how they deviate from the rates in the general populations. 

 Now we can compare to the data collected by the v-safe collection method described in the CDC report "COVID-19 vaccine safety update, Advisory Committee on Immunization Practices (ACIP)" cited above.

 The report makes a comparison for the COVID vaccines both to unvaccinated and vaccinated cases:



 The researchers found no significant difference here.

  However, the researchers in making a comparison to other vaccinated cases claimed also "no significant difference" while actually a sizable difference is apparent in the data for some adverse events:

  This illustrates a phenomenon criticized by statisticians that is common in some medical studies, where differences apparent in the data are disregarded as "not real" because the significance level does not reach the rather arbitrarily defined "0.5" level.
 
COMMENT  20 MARCH 2019
Scientists rise up against statistical significance.
Valentin Amrhein, Sander Greenland, Blake McShane and more than 800 signatories call for an end to hyped claims and the dismissal of possibly crucial effects.
Valentin Amrhein , Sander Greenland & Blake McShane

 
 This is actually a quite serious problem in medical studies: it results in life-saving drugs and life-threatening side effects being dismissed because of it.

 In scenarios like this, rather than dismissing the validity of the results, what it is actually signaling is that larger studies need to be done to strengthen the significance level. 

 In this particular case with the number of cases in the v-safe database of 800,000 it should be doable to get a quite high level of statistical significance to determine the validity of these numbers

   Robert Clark

 (Below the original blog post discussing the fact the vaccine companies and public health agencies have not released the safety data specifically for elderly patients.)

     __________________________________________________________

  I copied below some communications I had with the European Medicines Agency (EMA) through their online contact form about the safety of the COVID-19 vaccines specifically for elderly patients.

 After writing these, the question occurred to me, “Why am I having to go through this rigmarole to get the data that should be freely available about elderly recipients of the vaccine?”

 And I finally came to a stunning realization, "I'm being stonewalled."

 A large segment of the public is already skeptical about vaccines. This concern is worse now for new vaccines, and it’s even worse for a different kind of vaccine, and still worse again when the usual roll-out period of 5 to 10 years was shortened down to a single year. Then the vaccine manufacturers should be “purer than Caesar's wife”, in regards to the openness of their vaccine data.

 Yet the vaccine manufactures have not revealed the safety data specifically for elderly patients. And the impression I got from the EMA and also from the CDC is they are no more interested than the vaccine manufacturers in providing this information. 

 The conclusion that the vaccine companies are intentionally hiding the safety data for elderly recipients from the public was confirmed by this recent report:

Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England.
Jamie Lopez Bernal, et al.

 Every other report on the COVID-19 vaccines when they were discussing younger recipients, reported both the efficacy and safety of the vaccine.

 But in this report discussing elderly recipients, only the efficacy is reported, not the safety.

 Let this sink in for a minute:

 If you were to ask the CDC or the EMA or any other public health agency what is the safety profile for the COVID-19 vaccine specifically for elderly patients, their response would be, "We don't know."

 You don't have to believe me on this. I ask any doctor in any country anywhere in the world that specializes in treating elderly patients or oversees care in nursing homes to ask for this data.

 Here’s the CDC contact page:

 Here’s the EMA contact page:


 The contact person for the NEJM report by Pfizer on their vaccine trial is given here:


 It is possible that if your specialty is gerontology that they'll provide you this information since clearly in your case it would be extremely important to know that, but my guess is you'll be stonewalled too.



    Robert Clark


============================================
Re: [EXTERNAL:]AskEMA - Response to ASK-78662 - Safety of the Pfizer vaccine.

 I read the report you suggested [https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdfand found it was less informative than the NEJM article I was referencing in regards to adverse events. For instance it doesn't say that high fevers at > 38.9⁰C (102⁰F) temperatures occur at 0.8% of cases for the vaccine compared to 0.1% for the placebo.

 I have since read other reports that now make it imperative that Pfizer release a detailed safety report on 2nd dose AE's, classified by serious, severe, life-threatening, and fatal, as well as providing an analogously detailed safety report for elderly patients.

 Here's one of the reports I'm referring to:

Second COVID Shot Packs the Big Punch.
— First dose also worse for those with previous COVID, but "small price to pay" for protection.
by Kristina Fiore, Director of Enterprise & Investigative Reporting, MedPage Today February 11, 2021
https://www.medpagetoday.com/special-reports/exclusives/91157

 It details that healthcare workers commonly have to take off work because of side effects of the second dose. These are people of relatively good health, yet a large number are wiped-out after the 2nd dose, to the extent they have to take off a day or so to recover.

 Note that though Pfizer has acknowledged that a large percentage of recipients will experience some side effects, what's key here is these side effects in many will occur concurrently. So the common side effects of headache, fever, chills, fatigue will occur at the same time, effectively incapacitating them for a day or more.

 I had been concerned about the high fevers for the elderly but now knowing these adverse events can occur in combination it becomes even more worrisome considering the large percentage at which they occur. Younger, healthier people could weather this combination of symptoms, but elderly, frail patients may not be.

 Also, worrisome is that these symptoms, debilitating in combination, can also occur after just the 1st dose for patients who already had COVID-19. So this serious combination of symptoms could be life-threatening even after just the 1st dose for elderly patients if they had COVID-19 already.

 I don't know if this is the case in Europe but I know in the U.S. it's being recommended by health agencies that people who have had already COVID-19 should also get the vaccine. Again, for the elderly this could result in a life-threatening combination of symptoms after just the first dose, and for the young and healthy could be debilitating for a day or more.

 This also raises the possibility that those who had COVID-19 but were asymptomatic or with mild symptoms, not being aware they had it, could also suffer this serious combination of symptoms after just the first dose.

 This possibility of a life-threatening reaction for the elderly with prior COVID-19 after just the first dose may have been realized in the examples described in this report:

Deaths of Elderly Who Recovered From COVID-19, but Died After Vaccine, Raise Questions
Sharyl Attkisson
February 10, 2021 Updated: February 16, 2021 
https://www.theepochtimes.com/deaths-of-elderly-who-recovered-from-covid-19-but-died-after-vaccine-raise-questions_3692259.html 
{may require registration}

 We now know also the occurrence of the deaths in Norway nursing homes after  taking the vaccine was not an outlier but rather is now something occurring worldwide:

02/16/21
46 Nursing Home Residents in Spain Die Within 1 Month of Getting Pfizer COVID Vaccine
Health officials have reportedly halted administration of the second shot of Pfizer’s vaccine at the Spanish nursing home.
“The UK Medical Freedom Alliance — a group of doctors, scientists, lawyers and other professionals who advocate for informed consent in the UK — published an urgent open letter to Nadhim Zahawi, Minister for COVID-19 vaccine deployment; Matt Hancock, the Secretary of State for Health and Social Care; and two vaccine oversight agencies calling for an immediate audit of the deaths following vaccination in the UK.
The group refers to graphs showing a surge in care home deaths and cites data from the Office for National Statistics that residents’ deaths tripled in the two weeks between January 8- 22 at a time when there was a massive increase in the rate of vaccinations in care homes.

Similar graphs for Israel, Ireland, Bahrain and Jordan show a similar correlation.”
https://childrenshealthdefense.org/defender/nursing-home-residents-spain-die-pfizer-covid-vaccine/

  Given these examples, which apparently are common to both approved COVID-19 vaccines, both vaccine manufacturers should put out advisories making doctors aware of the possible dangers when used in these situations. 

    Robert Clark

___________________________

Robert Clark

Dept. of Mathematics

Widener University

One University Place

Chester, PA 19013 USA

___________________________

From: AskEMA No-Reply <AskEMA....@ema.europa.eu>
Sent: Friday, February 12, 2021 9:09 AM
To: Robert G Clark <rgc...@widener.edu>
Subject: [EXTERNAL:]AskEMA - Response to ASK-78662 - Safety of the Pfizer vaccine.
 
Dear Mr Clark

Thank you for your follow-up response regarding the safety of Comirnaty.

I am afraid there is not much I can add to our previous response. As noted there, we cannot comment on the information published in medical journals, which is a matter for them. Similarly, we cannot comment on what public information may or may not be available in other jurisdictions.

The side effects included in the licensed product information for the EU (https://www.ema.europa.eu/en/documents/product-information/comirnaty-epar-product-information_en.pdf) are based on the safety database in all patients given the licensed regimen in prelicensing studies and our information is increasingly being supplemented with real-world evidence from the millions of persons who have now received the vaccine. EMA will take any necessary regulatory action should a signal of new side effects or a change in frequency of known side effects in particular groups be confirmed.


Kind regards

**** ****, Stakeholders and Communication Division

European Medicines Agency
Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
Send us a question. Go to [http:://www.ema.europa.eu/contact]www.ema.europa.eu/contact Telephone: +31 (0)88 781 6000

____________________________________________________________

We received your question(s) on: 10/02/2021
Subject of your enquiry: Safety of the Pfizer vaccine.
Your question(s):
Thank you for your quick response. I will read the safety reviews you made. 

By the way, I can't remember if I mentioned this to you but among the fevers mentioned as occurring in the published report were also high fevers.

This is another key point that needs to be focused on. The Figure 2 of the report shows by bar graphs the number of fevers developed by vaccine recipients. In discussing that, they give this confusingly written passage:

Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger vaccine recipients and by 11% of older recipients. Only 0.2% of vaccine recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose. Two participants each in the vaccine and placebo groups reported temperatures above 40.0°C. Younger vaccine recipients were more likely to use antipyretic or pain medication (28% after dose 1; 45% after dose 2) than older vaccine recipients (20% after dose 1; 38% after dose 2), and placebo recipients were less likely (10 to 14%) than vaccine recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter.

The first sentence and the second sentence give different percentages for the number of patients who got what is called in both sentences just “fever”. It must be that what they call in the first sentence “fever” are just those with temperature ≥ 38°C. But in the second sentence they should have referred to the cases they are considering then as high fevers, because these are with temperatures ≥ 38.9°C, which is ≥ 102°F. Temperatures this high can be life-threatening for elderly patients as we know from the number of elderly patients who die in hospital after contracting pneumonia.

The passage I quoted says those with the high fevers was 0.8% for the vaccine group and 0.1% for the placebo group after the 2nd dose.

The data given doesn’t allow us to say how many of the elderly developed the high fevers, but if it were 0.8% of elderly patients getting a high fever after the 2nd dose that would be concerning. That would be 160 patients of the 20,000 in nursing homes in Norway who got the Pfizer vaccine.

For this reason, Pfizer should still be required to release the data to the public on the safety profile on the 2nd dose including the classification of the adverse events by serious, severe, life-threatening, and fatal.

And in addition a similar safety profile should be provided specifically for the elderly patients. 

Robert Clark

==========================================================

AskEMA No-Reply 
Tue 2/9/2021 2:14 AM
To: Robert G Clark

Dear Mr Clark

Thank you for your message to the European Medicines Agency (EMA) regarding the safety of the Pfizer/BioNTech COVID-19 vaccine, marketed in the EU as [Comirnaty|https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty]. You raise some concerns about the data provided in a published paper in the New England Journal of Medicine and ask whether EMA has information on the safety of the medicine after a second dose.

I must point out that it is important not to confuse the information presented in papers printed in medical journals, which will have been edited by the journal and adapted for publication, with the much fuller information provided to regulators for assessment. EMA is in receipt of a full data package for the medicine, which has been provided bit by bit over the course of a rolling review. This naturally includes assessment of safety in recipients who have had both indicated doses.

You can find a report of EMA’s scientific evaluation of the vaccine, including its assessment of safety, at: [https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf].

Because the medicine was granted a conditional marketing authorisation, one of a number of options available under EU pharmaceutical law, further information is expected to be provided over time. This includes input from the EU’s extensive pharmacovigilance monitoring system, which has been enhanced in the context of the mass vaccination campaigns expected for COVID-19 vaccines.

Regular safety summaries are being published to keep the public updated on new information regarding the safety of these medicines as we receive it, and the first such summary is available at: [https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-comirnaty-january-2021_en.pdf]. This addresses the issues reported in frail elderly individuals in Norway.

EMA also intends to publish the more detailed information it has from the clinical studies on its clinical data site ([https://clinicaldata.ema.europa.eu/web/cdp/home]) once this has been redacted of personal/confidential information.

We cannot comment on the specifics of the published paper in NEJM, but you might consider contacting the corresponding author should you wish to enquire further about the information provided therein.

I hope you find this information helpful. We would be grateful if you could take part in a short survey on our service, which you can access through the following link:

[https://ec.europa.eu/eusurvey/runner/AskEMA].

Kind regards

**** ****, Stakeholders and Communication Division
European Medicines Agency
Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
Send us a question. Go to [http:://www.ema.europa.eu/contact]www.ema.europa.eu/contact Telephone: +31 (0)88 781 6000

____________________________________________________________

We received your question(s) on: 03/02/2021

Subject of your enquiry: Safety of the Pfizer vaccine.

Your question(s):
Hello. I was quite concerned to read of the deaths in Norway after patients were given the Pfizer vaccine. It should be noted in this regard that Pfizer has not provided a complete safety profile for the 2nd dose of their vaccine during testing, only for the 1st dose. See the supplementary file to their published report here:

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Fernando P. Polack, M.D., et al.
December 31, 2020
N Engl J Med 2020; 383:2603-2615
DOI: 10.1056/NEJMoa2034577
https://www.nejm.org/doi/full/10.1056/NEJMoa2034577#article_supplementary_material

The table showing the safety profile after the 1st dose is Table S3 on page 9.

However, there does not appear in this supplementary file a similar safety profile after the 2nd dose.

The number of deaths of 23 after only 20,000 vaccinations in elderly patients in Norway is quite high. Given these deaths, Pfizer should be required to also reveal the safety profile after the 2nd dose.

Note though that Pfizer did provide a listing of adverse events for the 2nd dose in the paper itself in Figure 2:

https://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2020/nejm_2020.383.issue-27/nejmoa2034577/20210201/images/img_medium/nejmoa2034577_f2.jpeg

The omission I’m referring to is that in the supplementary file in Table S3 on page 9 the listing of adverse events is classified by serious, severe, life-threatening, or fatal, but this was only for the 1st dose. There was no corresponding table for the 2nd dose provided in the supplementary file.

 In the bar graphs in Figure 2 linked above they show the number of fevers was much higher than for placebos after the 2nd dose. These fevers could have serious consequences for the elderly patients.

Then Pfizer should be required to provide the safety profile for the 2nd dose where the adverse events are classified by serious, severe, life-threatening or fatal, as was done for 1st dose in Table S3, page 9 of the supplementary file.

Going beyond that, they should also be required to provide the adverse events and safety profile specifically for elderly patients for both the 1st and 2nd doses.

Quite frankly, I’m surprised a vaccine manufacturer can get approval to the general public for a new vaccine without presenting the full safety information on both the 1st and the 2nd doses of their vaccine. 

Am I correct in assuming if someone in the public asked the European Medicines Agency what’s the safety profile on the Pfizer vaccine after the 2nd dose their response would be, “We don’t know”? 

   Robert Clark

___________________________

Dept. of Mathematics
Widener University
One University Place
Chester, PA 19013 USA
___________________________
____________________________________________________________

Monday, February 1, 2021

Rapid identification of effective treatments for COVID-19.

Copyright 2021 Robert Clark

 

Cross-country Comparisons.

 There has been a present push to reopen the economies and the schools. Unfortunately, there has been a present surge in COVID-19 cases. Some countries particularly the Asian countries have COVID-19 death rates at 1/100th those in Western countries:

 Researchers ponder why covid-19 appears deadlier in the U.S. and Europe than in Asia.

https://www.washingtonpost.com/world/researchers-ponder-why-covid-appears-more-deadly-in-the-us-and-europe-than-in-asia/2020/05/26/81889d06-8a9f-11ea-9759-6d20ba0f2c0e_story.html

  We suggest an international conference on the treatments being used that have been found effective throughout the world. Such a conference could even be conducted online.

 Very few researchers seem to be giving this difference in COVID-19 fatality rates by country comparisons sufficient attention. It's importance though becomes even more clear when it's noted this radical reduction in fatality rates also applies in the African countries:


The pandemic appears to have spared Africa so far. Scientists are struggling to explain why.

  Many even knowledgeable researchers in the medical field are not even aware of it. I think the cross-country comparisons should be made to various influencing factors such as population age, obesity levels, mask wearing, lockdowns, prevalence of vaccines, medications common in a region due to endemic illnesses, and treatments.

 Commenters on this difference have mentioned the first few of these as the cause. But quite puzzling is the aversion of those who have commented on the question to consider the possibility that difference in treatments might at least be a part of cause.

  For instance one explanation offered is mask wearing common in Asian countries. But mask  wearing is not common in India or the African countries, with the low fatality rates. Another explanation given is the greater testing in Asian countries, but Indonesia has one of the lowest rates of testing:

 https://www.thejakartapost.com/news/2020/04/07/indonesia-ranks-among-worlds-worst-in-coronavirus-testing-rate.html

  Yet still Indonesia counts with the other Asian countries as among the lowest in fatality rates.

  Asia and Africa together account for 3/4ths of the world's population. That they have orders of magnitude lowered death rates suggest all factors including treatment strategies should be considered in evaluation which of these to adopt in Western countries.

 Antivirals.

 It is a well-known fact that antiviral therapies are best applied soon after infection, for example, for influenza and HIV. And this had been the recommendation of the CDC against the flu and the pandemic H1N1:


Revised CDC guidance on flu antivirals stresses early treatment.
Filed Under: Influenza, General; H1N1 2009 Pandemic Influenza; Public Health
By: Robert Roos  | Sep 08, 2009
Sep 8, 2009 (CIDRAP News)  Revised recommendations from federal health officials on the use of influenza antiviral drugs suggest that clinicians consider providing prescriptions over the phone for high-risk patients as a way to start treatment faster if they come down with flu symptoms.
 At the same time, the recommendations released today from the Centers for Disease Control and Prevention (CDC) suggest that clinicians try "watchful waiting" when high-risk patients have been exposed to flu but remain healthy, rather than prescribing a preventive antiviral right away. The recommendations cover both pandemic H1N1 and seasonal flu.
https://www.cidrap.umn.edu/news-perspective/2009/09/revised-cdc-guidance-flu-antivirals-stresses-early-treatment

  Oddly, this lesson seems to have been forgotten for COVID-19.

  This article argues for going back to that well-known principal of antiviral therapies:


Rethinking antiviral effects for COVID-19 in clinical studies: early initiation is key to successful treatment.
Shoya Iwanami, et. al.
https://www.medrxiv.org/content/10.1101/2020.05.30.20118067v1

   Recently, the NIH in an article co-authored by Fauci advocated for finding medications effective for early treatment for COVID-19:


November 11, 2020
Therapy for Early COVID-19
A Critical Need
Peter S. Kim, MD1; Sarah W. Read, MD, MHS1; Anthony S. Fauci, MD2
JAMA. 2020;324(21):2149-2150. doi:10.1001/jama.2020.22813
https://jamanetwork.com/journals/jama/fullarticle/2773058

  Note they are making this recommendation even considering the vaccines now coming into use. However, it is utterly mystifying why the NIH came so late to this realization since it is a well-fact about antivirals that they are most effective early. Indeed, in the early part of the year, before the vaccines were developed, it was even more important to have such early antiviral treatments but the NIH made no such recommendations to find them.

  So we have had numerous clinical studies supported by the NIH on late treatment using antivirals such as HCQ, Remdesivir, lopinavir/ritonavir, interferon, ribavirin, etc. When these were shown ineffective in studies for late treatment, the unfortunate inference drawn by many was that they were in general ineffective against COVID-19. This led to their not even being tried for the scenario they from the beginning should have been tried for, early treatment, soon after symptoms appear.

  There have been many antivirals that have been shown effective against the coronavirus in vitro, but have been disappointing in vivo. But almost all such studies have been looking at patients at advanced disease. But key would be to do the treatment soon after symptoms first appear. Because testing sometimes takes days for the results to come back, the treatment should be applied immediately even before a positive test confirmation.

  Because there are sometimes false negatives, the medication should continue to be taken during the time symptoms are apparent. And even if after repeated testing it is likely the person is negative for COVID-19, if the medication is effective than it should be protective during the period the medication is taken. This in fact will be another method of testing its effectiveness, by determining if it has a protective effect.

 Since such treatments are taking place before serious disease develops it necessarily would be on an outpatient basis. Then for those antivirals being taken among the teams administering the medications there should be experts on the possible side effects.

 To be able to find which medications are most effective, clinical practices and hospitals within the same general vicinity could be using different medications. That would be able to make it easier to compare their effectiveness, without various confounding factors coming into play. And the effectiveness of the medications should be shared in real time.

 A difficulty with respect to COVID-19 though is that most subjects recover on their own making it difficult to see if a medication is having a real effect or not. However, the experience of some doctors in Italy with hydroxychloroquine shows a key and important method by which the effectiveness could be detected: cut in hospitalizations.

 Success in Italy reported in early treatment of COVID-19 using hydroxychloroquine.

https://exoscientist.blogspot.com/2020/05/success-in-italy-reported-in-early.html

  Since most deaths come after hospitalizations a dramatic cut in hospitalizations would result in a dramatic cut in the death rates. And the experience of those particular doctors in Italy using it was of a dramatic cut in the hospitalizations. Unfortunately, restrictions on its use are in place in Italy as it is in U.S. and most Western countries so it cannot be determined for sure if the effectiveness seen by these doctors will be a general phenomenon.

  The importance of this early use, for HCQ and other proposed antivirals, is not just for the cut in the hospitalizations but also the speed at which this drop will become apparent. If you are only judging by death counts, then that can take weeks to months to determine the medications effectiveness because patients can remain hospitalized for weeks to months, before it is determined if they recover or not from the disease.

  But because for COVID-19 whether the disease progresses to the serious stage requiring hospitalization is determined within a matter of days, doctors using the medication would know within days if it is effective in cutting the hospitalizations they observed.

  If an antiviral is effective against COVID-19 then the same should be true also for that antiviral, a cut in hospitalizations that becomes apparent within days.

  Given the success those particular doctors in Italy using it for early treatment have found in cutting hospitalizations, hydroxychloroquine should be among the antivirals being tried. However, the FDA has a policy in place that is interpreted as banning it in general for treating COVID-19. But actually the policy allows it within clinical trials against COVID-19. But any doctor can apply for a clinical trial. So the doctors wanting to use it should apply to conduct a clinical trial. Such trials don't have to be paid for by government grants or pharmaceutical companies. And the medication itself is quite cheap. Only, those doctors wanting to use it should have doctors on their teams or be in consultation with doctors who are experts in their use and possible side effects such as those specializing in rheumatic diseases.

  Note that what is being argued for here is a process for finding and testing medications known as Real World Experience(RWE). In the midst of an epidemic during its exponential growth phase, RWE's might be the best approach to take rather than RCT's for finding treatments.

 

 Randomized Controlled Trials(RCT's) commonly take 3 months or more to complete, and then there still can be complaints it didn't have enough study participants to form firm conclusions. Here I'm arguing for RWE's, but conducted nationwide.

 

 An advantage of RCT's is their randomized nature allows confounding factors to be accounted for. But RWE's conducted nationwide can accomplish the same thing because of the large number of cases and circumstances of the studies.

 

 Indeed several authors have argued for these reasons for RWE's:

May 11, 2018,12:25am EDT

Will Real World Performance Replace RCTs As Healthcare's Most Important Standard?

David Shaywitz Contributor

Healthcare

https://www.forbes.com/sites/davidshaywitz/2018/05/11/will-real-world-performance-replace-rcts-as-healthcares-most-important-standard/

 

The Beneficial Impacts of Real-World Evidence in Drug Development

Posted on August 1st, 2019 by Xuanyan Xu in Pharma R&D

Real-world evidence, which is based on data that is gathered during routine clinical practice, has the potential to make a meaningful impact in nearly every phase of the life of a drug. That means RWE is relevant to:


Early discovery – “RWE has the potential to be used early in drug discovery and development programs, facilitating product development by identifying diseases or indications that represent a significant burden in populations,” explains this paper on real-world evidence, also noting the example of the NIH using electronic health records to support differentiation of patients’ needs.

...

https://pharma.elsevier.com/pharma-rd/the-beneficial-impacts-of-real-world-evidence-in-drug-development/


Version 2. F1000Res. 2018; 7: 111.
Published online 2018 Aug 29. doi: 10.12688/f1000research.13585.2
Real world evidence (RWE) - a disruptive innovation or the quiet evolution of medical evidence generation?
Sajan Khosla 1, Robert White 2, Jesús Medina 3, Mario Ouwens 4, Cathy Emmas 5, Tim Koder 6, Gary Male 6, Sandra Leonard 2
PMID: 30026923 PMCID: PMC6039945 DOI: 10.12688/f1000research.13585.2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039945/

  Note with doctors nationwide using their own judgement and experience about which medications to use, we would have orders of magnitude greater insight about which medications could be effective rather than just restricting to a few doctors on a few teams conducting RCT’s. 

 Doctors whose expertise is in rheumatic diseases for example could prescribe HCQ. They would be intimately familiar with its side effects and would know what to look for. And doctors for example who routinely prescribe interferon would know its side effects and contraindications. This way you could have a maximal safety approach while allowing a wide variety of different medications to be tested at the same time.

 There are about a million doctors in the U.S. Imagine all that knowledge, all that experience, all that creativity, all being brought to bear in toto in finding effective treatments for this, and other diseases as well. Furthermore, imagine this all happening in real time, critically important in the midst of a pandemic.

  It is notable then there have been antivirals found effective in trials for early treatment. One is interferon:


Thursday, April 9, 2020
A new possible treatment for COVID-19: interferon alpha.
http://exoscientist.blogspot.com/2020/04/a-new-possible-treatment-for-covid-19.html

Nebulised interferon beta-1a for patients with COVID-19.
Nathan Peiffer-Smadja, Yazdan Yazdanpanah
Published:November 12, 2020
DOI:https://doi.org/10.1016/S2213-2600(20)30523-3
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30523-3/fulltext

 Another is favipiravir for early treatment:


Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19.
Posted: 26 Oct 2020
Tatiana Ruzhentsova, Pavel Chukhliaev, et.al.
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3696907


International Journal of Infectious Diseases.
November 16, 2020
Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3  Clinical Trial
Zarir F.Udwadiaa, et.al.
https://www.sciencedirect.com/science/article/pii/S120197122032453X

 

 It is notable, and unfortunate, that these successful trials showing effective antiviral use when used early occurred in trials overseas.

  Even more dismaying is that there were published reports early on in the timeline of the disease in the U.S. that showed early treatment was effective using antivirals, such as this report from May from China:


ARTICLES| VOLUME 395, ISSUE 10238, P1695-1704, MAY 30, 2020
Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial
Prof Ivan Fan-Ngai Hung, MD et al.
Published:May 08, 2020
https://doi.org/10.1016/S0140-6736(20)31042-4

  Most of these reports were from Asian countries, but that's hardly a reason to disregard their validity. It is truly puzzling that these successful results on early treatment in Asia were not followed up upon with American and European studies also on early treatment. Instead, mystifyingly, the studies taken up in the West using these antivirals were for patients under late stages of the disease, where it was already known antivirals were not likely to be effective.

Anti-inflammatories for serious disease.

 Some anti-inflammatories have shown to be effective for patients that need oxygen such as those on ventilators, including dexamethasone and tocilizumab. But the reduction in lung inflammation can be measured in real time by detecting markers such as IL-6 and CRP and even in CT scans. Then the effectiveness of these anti-inflammatories can also be observed on short time scales. See the discussion in the update dated from 6/26/2020 here:


About the article, “Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19”. UPDATED, 6/26/2020.
https://exoscientist.blogspot.com/2020/06/about-article-observational-study-of.html

 There, is discussed this report:


Research Paper
Published: 15 May 2020
Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19.
Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang, Jia Li, Hualiang Jiang & Dao-Wen Wang
Science China Life Sciences (2020)
Abstract
...
These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.
hydroxychloroquine, IL-6, mortalities, COVID-19
https://link.springer.com/article/10.1007/s11427-020-1732-2

 Quite notably the authors observed in real time a reduction in the level of IL-6, a key marker for inflammation, during the treatment with HCQ. So from both CT imaging and inflammation marker readings we could tell if HCQ or other anti-inflammatories were having a beneficial effect on patients under severe disease.

 It is important to understand the reason why it was that several studies from Asian countries showed positive effects for HCQ while several studies in the Western countries did not.

 After we examined several of the negative reports on HCQ published on Western studies, we observed multiple times that the effectiveness of  HCQ was obscured in the presentation of their data. We will offer no hypotheses as to the reasons why its effectiveness was obscured in the reports on the Western studies.

 For example, two of the most widely-cited negative HCQ reports by Geleris et al. and Rosenberg et al. omitted from the conclusions that the data showed HCQ cut mortality in half for ventilated patients. Adverse events for a medication must be reported, and this has been done extensively for HCQ. But by the same token, subcases with benefit for the medication should also be reported.

 

 The report by Geleris et. al. here:

 

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.

June 18, 2020

Editor’s Note: This article was published on May 7, 2020, at NEJM.org.

N Engl J Med 2020; 382:2411-2418

DOI: 10.1056/NEJMoa2012410

https://www.nejm.org/doi/full/10.1056/NEJMoa2012410

 

 Left out of the paper itself, and included only in the Supplementary Appendix, was this Table:

https://www.nejm.org/doi/suppl/10.1056/NEJMoa2012410/suppl_file/nejmoa2012410_appendix.pdf

 You see the mortality in the HCQ group for intubated patients, i.e., those on invasive mechanical ventilation, was 49/154 = .318, or 31.8%. But the mortality for intubated patients for the non-HCQ group was 17/26 = .654, or 65.4%. So the mortality was halved in the HCQ group for intubated patients.

 Actually, it may even be better than this. As an observational trial, the treated patients are likely not evenly distributed among patients with different comorbidities or with level of disease compared to the controls. Quite often the treatments are given to the sicker patients. Then usually in such observational studies as in this one statistical adjustments have to be made to compensate for the fact the sicker patients were given the medication which would skew the results against the treated group.

 But in the Table S1 this appears to be just the raw data. Then after the statistical adjustments for HCQ being given to the sicker patients the mortality benefit for HCQ over the controls for ventilated patients might be even higher.

 The Rosenberg et. al. paper is here:


May 11, 2020
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
Eli S. Rosenberg, PhD1; Elizabeth M. Dufort, MD2; Tomoko Udo, PhD1; et al
JAMA. 2020;323(24):2493-2502. doi:10.1001/jama.2020.8630
https://jamanetwork.com/journals/jama/fullarticle/2766117

 The table showing the mortality specifically for ventilated patients from the supplementary file here:


 You see HCQ used alone reduced mortality specifically for ventilated patients by a factor of 0.60 and HCQ used with AZT by a factor of 0.53.  But once again this appeared not in the paper itself but only in a supplementary file.

 It's dismaying that this data wasn't discussed among the conclusions the authors made in their articles. First of all appearing only in the supplementary files, not in the articles proper, very few people would have taken the time to find and read these tables, certainly not the science journalists reporting on the research and not even most doctors disseminating this information to the public at large and to the policy makers making decisions on use of HCQ.

 But what's really dismaying is both of these took place in New York. In New York at the time the mortality for patients on ventilators was in the range of 80%:

A bridge between life and death: Most COVID-19 patients put on ventilators will not survive.
John Bacon
USA TODAY       Updated  April 10, 2020
https://www.usatoday.com/story/news/health/2020/04/08/coronavirus-cases-ventilators-covid-19/2950167001/

 Doctors were desperate to find a treatment to help save ventilated patients lives, but the effectiveness of HCQ for those on ventilators was not made apparent to them.

 The usefulness of HCQ for those on mechanical ventilation would have been even more apparent because of that report appearing in a Chinese journal that we cited above by Bo Yu et al., "Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19".

 That report showed mortality cut by 60% for ventilated patients taking HCQ. But with the two widely cited American papers making a blanket statement of "no benefit", this Chinese report barely registered.

 It's possible the authors and/or reviewers and/or editors calculated the significance levels and decided they didn't rise to the standard significance level of 0.05. If they did calculate the significance levels then they should have been reported in the papers. But in any case, all medical researchers are aware of the fact that a result not rising to statistical significance level does not mean the result is wrong. It could also simply mean the sample size wasn't large enough for it to rise to statistical significance.

 All too often this qualifier is left out of reports on medical studies, and it is certainly left out on news reports on the studies. Then the public and other doctors are simply left with the incorrect conclusion that the treatment has been proven not to work.

 With a difference this large of the deaths being cut in half for those on ventilators, the significance levels should have been reported in the papers. And it should have been acknowledged in the papers if the significance level wasn't at the standard level of 0.05 for the sample size used, that larger studies would be needed to determine if the result was real or just a statistical artifact.

 
 As we mentioned, studies have shown multiple different anti-inflammatories such as steroids can be beneficial for COVID-19. Indeed this happened with dexamethasone in the RECOVERY trial, among others. It is simply unreasonable then to suppose HCQ as a very effective anti-inflammatory is not. It’s probably the reason so many HCQ studies, including ones claiming “no benefit”, did show benefit.

 An astonishing instance of this occurred in the RECOVERY trial. The RECOVERY trial was a randomized-controlled trial (RCT), which are called the "gold-standard" of medical studies. Because it was negative towards HCQ, it was frequently cited as evidence of HCQ having no effect.

 RCT's aren't perfect of course. There can be flaws in interpreting the data, there may not be sufficient numbers of subjects to draw a strong conclusion. They can use the wrong dosage, etc. And unfortunately there can also be cases where researchers falsify data.

 We do not consider this last possibility likely to be the case with the RECOVERY trial. However, what we found did happen in the RECOVERY trial was nearly as bad in regards to accurately assessing the effectiveness of HCQ: while the data presented was correct, the way it was presented obscured the HCQ effectiveness.

 Here's the HCQ report from the RECOVERY trial:

Editor’s Note: This article was published on October 8, 2020, at NEJM.org.
ORIGINAL ARTICLE
Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group
November 19, 2020
N Engl J Med 2020; 383:2030-2040
DOI: 10.1056/NEJMoa2022926
https://www.nejm.org/doi/full/10.1056/NEJMoa2022926

  Here's the relevant table:


  You see instead of deaths on mechanical ventilation being given directly, it is combined with all deaths into one category. This is called a "composite endpoint" or "composite outcome". So, we need to do the calculation to find the proportion of the ventilated patients who died on HCQ and then calculate the proportion for those not on HCQ who died, since these are not given directly. Use the formula for counting the number of elements in the union of two sets with possible overlap:

which simply means you add together the number in each set, then subtract off the number in the overlap.

 What's given in the report is the union of the two sets of the ventilated and of the deaths. But what we want is the intersection, those who were ventilated that died. So we'll turn around that formula for the number in the union to get the number in the intersection as, | A B | = |A| + |B| - | A B |.

 So in this case, |ventilated deaths| = |ventilated| + |deaths| - |ventilated deaths|.  First look at the cases on HCQ. From Table 2, for those on HCQ,  |ventilateddeaths| = |ventilated| + |deaths| - |ventilated deaths| =128+311- 399 = 40. So on HCQ, the rate of deaths on ventilator 40/128 = 0.312, 31.2%.

 Now calculate it for the non-HCQ group, i.e., the usual care group. The numbers appear in the "Usual care" column in the table. So in this case, |ventilated deaths| = |ventilated| + |deaths| - |ventilated deaths|.  First look at the cases on HCQ. From Table 2, for those HCQ,  |ventilateddeaths| = |ventilated| + |deaths| - |ventilated deaths| = 225 + 574 - 705 =  94, so the rate of deaths on ventilator is 94/225 = 0.417, or 41.7%.  This difference between the number of ventilated patients on HCQ who died of  32.2% and those not on HCQ who died of 42.3% is large enough that it should have been reported.

 The RECOVERY trial made headlines world-wide when it sent out a news release on the "breakthrough" that the steroid dexamethasone could cut mortality for ventilated patients by 30%.

 Here is the published article on the discovery:

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report.
The RECOVERY Collaborative Group
July 17, 2020DOI: 10.1056/NEJMoa2021436
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436

 In the Results section the mortality for ventilated patients on dexamethasone is given as 29.3%, while for those not on dexamethasone it's given as 41.4%. Note these numbers are quite close to those for HCQ. Yet the RECOVERY trial described HCQ as offering "no benefit" while dexamethasone was described as a "breakthrough".

 Note that all of the Geleris et al., Rosenberg et al., and the RECOVERY trials could legitimately report that overall there was no statistical difference by using HCQ. But this was because for the important subcase of ventilated patients, their numbers were a small proportion of the total number of cases. However, the large difference using HCQ for that key subcase of ventilated patients should have been reported.

 Another instance where positive effects of HCQ were obscured was in a paper by Tang et al. In this case though the positive effects weren't just obscured, they were actually deleted:

 

Research
Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1849 (Published 14 May 2020)
https://www.bmj.com/content/369/bmj.m1849

  Tang et al. is regarded as a negative HCQ paper, but deleted from the published version was this passage in the preprint:


Title: Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial.
"In addition to virus infection, acute inflammation response is another hallmark of COVID-19.19
Recent findings in clinical series have shown that the systemic inflammation or cytokine storm is
the driver of disease progression and death.20,21 Substantially decrease of lymphocyte count and increase of inflammatory response marker, e.g., CRP were both observed in the early stage of patients who eventually progressed and died.21 These results highlighted the importance of the recovery of lymphopenia or anti-inflammation in preventing the development of systemic
inflammation in critically ill COVID-19 patients. Such abilities and benefits were observed from
HCQ in our current trial, showing that patients with SOC plus HCQ had a significantly greater
reduction of CRP level and a moderate elevation of blood lymphocyte count at the last assessment comparing to patients with SOC only. These effects were observed after 5-day of HCQ treatment and maintained until the withdraw of HCQ. These encouraging results suggested clinical benefits of adding HCQ into the current standard management to limit inflammatory response, which is the key to prevent systemic inflammation and subsequent multiple organ failure and death."
https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1.full.pdf  

 The extensive list of benefits of HCQ seen by the Tang et al. research group, that were deleted from the published report was discussed by Dr. Didier Raoult here:


TANG ET AL, BMJ: Favourable data for hydroxychloroquine removed between study’s draft and final print.
https://www.palmerfoundation.com.au/tang-et-al-bmj-favourable-data-for-hydroxychloroquine-removed-between-studys-draft-and-final-print/

 It is extremely unfortunate these details were deleted from the final report. Note this study appeared around the same time as the Geleris et al. and Rosenberg et al. reports in May. Since it shows HCQ effectiveness as an anti-inflammatory, if the Tang  published report and the two Geleris and Rosengberg published reports had revealed these positive effects of HCQ, then coupled with the positive results of the Bo Yu et al. report, doctors would have had an effective treatment approach to ventilated patients.

 Some Western doctors and researchers may choose to believe the Western studies rather than the Asian studies. But given the fact the death rates in the Asian countries are 1/100th those in the West, I would not be so sanguine about that choice.

 As with the antivirals, the Real World Experience approach should be used, with nearby hospitals testing different anti-inflammatories so the comparisons can be made to their effectiveness without confounding factors. And as with the antivirals the comparisons among the various hospitals should be done in real time. And also as with the antivirals the effectiveness of the anti-inflammatories might be seen within days by looking in real-time the presence of the inflammation markers such as IL-6 and CRP, and at the CT scans. The importance of the CT scans is that the improvement in the degree of lung inflammation can literally be seen by the doctors as the treatment progresses:

CT Provides Best Diagnosis for Novel Coronavirus (COVID-19)
CT scans can detect coronavirus in patients before RT-PCR lab testing
NEWS | COMPUTED TOMOGRAPHY (CT) | FEBRUARY 26, 2020 | MELINDA TASCHETTA-MILLANE AND DAVE FORNELL
In a study of more than 1,000 patients published in the journal Radiology, chest CT outperformed lab testing in the diagnosis of 2019 novel coronavirus disease (COVID-19)


Chest CT images of a 29-year-old man with fever for 6 days. RT-PCR assay for the SARS-CoV-2 using a swab sample was performed on Feb. 5, 2020, with a positive result. (A column) Normal chest CT with axial and coronal planes was obtained at the onset. (B column) Chest CT with axial and coronal planes shows minimal ground-glass opacities in the bilateral lower lung lobes (yellow arrows). (C column) Chest CT with axial and coronal planes shows increased ground-glass opacities (yellow arrowheads). (D column) Chest CT with axial and coronal planes shows the progression of pneumonia with mixed ground-glass opacities and linear opacities in the subpleural area. (E column) Chest CT with axial and coronal planes shows the absorption of both ground-glass opacities and organizing pneumonia. Image courtesy of Radiology 
https://www.itnonline.com/content/ct-provides-best-diagnosis-novel-coronavirus-covid-19

Research | Open Access | Published: 12 August 2020
Rapid identification of COVID-19 severity in CT scans through classification of deep features.
Zekuan Yu, Xiaohu Li, Haitao Sun, Jian Wang, Tongtong Zhao, Hongyi Chen, Yichuan Ma, Shujin Zhu & Zongyu Xie
BioMedical Engineering OnLine volume 19, Article number: 63 (2020)
https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-020-00807-x
 

 The observational difference in the appearance of coronavirus inflamed areas of the lung are made apparent in this 3D  CT scan:

CT scan shows damaged tissue from a covid-19 patient's lungs.

Apr 1, 2020



CT scans however use much more radiation than usual X-rays. Since this approach would require taking frequent CT scans of patients, methods of using reduced radiation as by Dr. Marcus Chen, may be preferred:


NHLBI Bethesda Labs
@TheBethesdaLabs
Dr. Marcus Chen's research involves making #CT scans safer by reducing the amount of radiation by over 90%. This chest CT shows a stunning view of a #COVID19 patient's lungs. The yellow areas represent normal lung tissue, while the blue areas are damaged tissue. #ImageOfTheWeek


3:12 PM · Aug 5, 2020·Twitter Web App

https://twitter.com/TheBethesdaLabs/status/1291089590191894528?s=20



 

   

   Robert Clark

 

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Department of Mathematics

Widener University

Chester, PA 19013

rgc0300@widener.edu

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