2021-01-22

VK kísérleti ótások

 

Műveletek

Doshi

 

Peter Doshi: A Pfizer és a Moderna „95% -ban hatékony” oltásai - további részletekre és a nyers adatokra van szükségünk

Öt héttel ezelőtt, amikor kérdéseket vetett az eredményeket a Pfizer és a Moderna a covid-19 vakcina kísérletek, minden, ami a nyilvánosság volt a vizsgálati protokollok és néhány sajtó sajtóközlemények . Ma két folyóirat publikáció és mintegy 400 oldalas összefoglaló adatok állnak rendelkezésre formájában több jelentések bemutatott által és az FDA megelőzően az ügynökség sürgősségi engedélyt minden egyes cég mRNS vakcina. Bár a további részletek némelyike ​​megnyugtató, némelyik nem. Itt új aggályokat vázolok fel a jelentett hatékonysági eredmények megbízhatóságával és értelmességével kapcsolatban.

„Covid-19 gyanúja”

Minden figyelem a drámai hatékonysági eredményekre összpontosult: Pfizer 170 PCR-rel igazolt covid-19 esetet jelentett, 8–162 osztva a vakcina és a placebo csoport között. De ezek a számok eltörpültek a „gyanús covid-19” nevű betegségkategóriában - olyanok, akiknél tüneti covid-19 volt, és amelyeket PCR nem erősített meg. Az FDA Pfizer oltóanyagról készített jelentése szerint „3410 gyanús, de meg nem erősített covid-19 eset volt a teljes vizsgálati populációban, 1594 fordult elő az oltóanyag-csoportban, míg 1816 a placebo-csoportban”.

A megerősített esetek 20-szor több gyanúja esetén a betegség ezen kategóriáját nem lehet figyelmen kívül hagyni pusztán azért, mert nem volt pozitív PCR-teszt eredmény. Valójában ez még sürgetőbbé teszi a megértést. A vakcina hatékonyságának durva becslése a covid-19 tünetek kialakulása ellen, pozitív PCR-vizsgálati eredménnyel vagy anélkül, 19% -os relatív kockázatcsökkenést jelentene (lásd a lábjegyzetet) - messze szabályozók által az engedélyezésre megállapított 50% -os hatékonysági küszöb alatt . A vakcinázás hatékonysága továbbra is alacsony: 29% a vakcinázástól számított 7 napon belül bekövetkezett esetek eltávolítása után (409 Pfizer oltással szemben, 287 placebóval szemben), amelynek tartalmaznia kell a tünetek túlnyomó részét a vakcina rövid távú reaktogenitása miatt (lásd a lábjegyzetet).

Ha ezek közül a gyanús esetek közül sok vagy többnyire olyan embereknél fordul elő, akiknek hamis negatív PCR-tesztje van, ez drámai módon csökkentené a vakcina hatékonyságát. De tekintve, hogy influenzaszerű megbetegedések is mindig volt számtalan oka -rhinoviruses, influenza vírusok, egyéb koronavírusokból adenovírusok légúti óriássejtes vírus, stb néhány vagy sok a gyanús covid-19 eset miatt lehet más kórokozót.

De miért számít az etiológia? Ha a „covid-19 gyanúja” tapasztalatai lényegében megegyeznek a klinikai lefolyással, mint a megerősített covid-19, akkor a „feltételezett plusz megerősített covid-19” klinikailag értelmesebb végpont lehet, mint a csak megerősített covid-19.

Ha azonban a megerősített covid-19 átlagosan súlyosabb, mint a gyanús covid-19, akkor is szem előtt kell tartanunk, hogy a nap végén nem az átlagos klinikai súlyosság számít, hanem a súlyos kórképek előfordulása, amely a kórházat érinti felvételi. 20-szor több gyanúsított covid-19-gyanúval, mint a megerősített covid-19-vel, és azokat a kísérleteket nem tervezték, amelyek felmérnék, hogy a vakcinák képesek-e megszakítani a vírusfertőzést, a súlyos betegség elemzése, függetlenül etiológiai tényezőtől - nevezetesen a kórházi ápolások, az intenzív osztályon esetek és a halálozások aránya a vizsgálat résztvevői - indokoltnak tűnik, és ez az egyetlen módja annak, hogy felmérjék az oltóanyagok valódi képességét a pandémia előretörésére.

Egyértelműen szükség van adatokra a kérdések megválaszolásához, de a Pfizer 92 oldalas jelentése nem említette a 3410 „gyanúsított covid-19” esetet. Az sem annak közzétételét a New England Journal of Medicine . A Moderna oltásról szóló jelentések egyike sem. Az egyetlen forrás, amelyről úgy tűnik, hogy arról számolt be, az FDA felülvizsgálata a Pfizer oltásáról.

A Pfizer vakcina hatékonysági elemzéséből kizárt 371 egyént

Egy másik ok, amelyre további adatokra van szükségünk, egy megmagyarázhatatlan részlet elemzése, amely megtalálható az FDA Pfizer oltóanyagának áttekintésében található táblázatban : 371 személyt kizártunk a hatékonysági elemzésből a „fontos protokoll-eltérések miatt a 2. dózist követő 7 napon belül”. Ami a véletlenszerű csoportok közötti egyensúlyhiányt illeti ezen kizárt egyének számában: 311 a vakcinacsoportból, szemben 60 a placebóval. (Ezzel szemben a Moderna-vizsgálatban csak 36 résztvevőt vettek ki a „fő protokolleltérés” hatékonysági elemzéséből - 12 vakcinacsoport és 24 placebo csoport.)

Melyek voltak ezek a protokoll-eltérések Pfizer tanulmányában, és miért volt ötször több résztvevő kizárva a vakcinacsoportból? Az FDA jelentése nem mondja, és ezeket a kizárásokat még a Pfizer jelentésében és folyóirat-kiadványában is nehéz észrevenni .

Láz- és fájdalomcsillapító gyógyszerek, a vakítás megszüntetése és az elsődleges események elbírálási bizottságai

A múlt hónapban aggodalmamnak adtam hangot a fájdalom- és lázcsillapítók lehetséges zavaró szerepe miatt a tünetek kezelésében. Feltételeztem, hogy az ilyen gyógyszerek elfedhetik a tüneteket, ami a covid-19 esetek aluldetektálásához vezethet, valószínűleg nagyobb számban azoknál az embereknél, akik a vakcinát a nemkívánatos események megelőzése vagy kezelése érdekében kapták. Úgy tűnik azonban, a bennük rejlő lehetőségeket, hogy megszégyenítse eredmények meglehetősen korlátozott volt: bár az eredmények azt mutatják, hogy ezek a gyógyszerek vették körül 3 - 4 -szer gyakrabban vakcina versus placebót kapó (legalábbis a Pfizer oltóanyag-Moderna nem jelentette egyértelműen), valamint az a felhasználás feltehetően az oltás alkalmazását követő első héten koncentrálódott, az injekció utáni helyi és szisztémás mellékhatások enyhítésére. De a halmozott előfordulás görbék a megerősített covid-19 esetek meglehetősen állandó arányára utalnak az idő múlásával, a tünetek megjelenési dátumai jóval meghaladják az adagolást követő egy hétet.

Ez azt jelenti, hogy az oltási ágban alkalmazott gyógyszerek magasabb aránya további okot ad a nem hivatalos vakítás aggodalmára. Tekintettel a vakcinák reaktogenitására, nehéz elképzelni, hogy a résztvevők és a kutatók nem tudtak kitalált találgatásokat kitalálni arról, hogy melyik csoportba tartoznak. A vizsgálatok elsődleges végpontja a viszonylag szubjektív, ami fontos aggodalomra ad okot a vakítás megszabadításában. Úgy tűnik azonban, hogy sem az FDA, sem a vállalatok hivatalosan nem vizsgálták meg a vakítási eljárás megbízhatóságát és annak hatásait a jelentett eredményekre.

Az elsődleges eseménybíráló bizottságok folyamatairól sem tudunk eléggé, amelyek a covid-19 eseteket számlálták. Vakítottak az antitest adatokra és a betegek tüneteire vonatkozó információkra az oltást követő első héten? Milyen kritériumokat alkalmaztak, és miért volt szükség egy ilyen bizottságra egy olyan elsődleges esemény esetén, amely a beteg által jelentett eredményből (covid-19 tünetek) és a PCR teszt eredményéből állt? Fontos megérteni azt is, hogy kik voltak ezekben a bizottságokban. Míg a Moderna megnevezte négytagú elbíráló bizottságát - az összes egyetemhez tartozó orvos -, a Pfizer protokollja szerint a Pfizer három alkalmazottja végezte el a munkát. Igen, a Pfizer munkatársai.

Vakcina hatékonysága olyan embereknél, akiknél már volt covid

Azokat a személyeket, akiknek a kórtörténetében ismert a SARS-CoV-2 fertőzés vagy a Covid-19 korábbi diagnózisa, kizárták a Moderna és a Pfizer kísérleteiből. De a Pfizer és a Moderna-vizsgálatok résztvevőinek 1125 ( 3,0% ) és 675 ( 2,2% ) résztvevőjét pozitívnak tekintették a kiindulási SARS-CoV-2 szempontjából.

Az oltások biztonságossága és hatékonysága ezekben a befogadókban nem kapott különösebb figyelmet, de mivel sok ország lakosságának egyre nagyobb része „poszt-Covid” lehet, ezek az adatok fontosnak tűnnek - és annál is inkább, mivel az amerikai CDC azt javasolja, hogy oltást kínáljanak korábbi tüneti vagy tünetmentes SARS-CoV-2 fertőzés története. ” Ez az ügynökségnek a Pfizer oltóanyaggal kapcsolatos következtetéseiből következik , hogy annak ≥92% -os hatékonysága volt, és „nincsenek különleges biztonsági aggályai” a korábbi SARS-CoV-2 fertőzésben szenvedőknél.

Számlálásom szerint Pfizer nyilvánvalóan 8 megerősített, tüneti Covid-19 esetről számolt be azoknál az embereknél, akiknél a kiinduláskor pozitív volt a SARS-CoV-2 (1 a vakcinacsoportban, 7 a placebo csoportban, a 9. és 10. táblázat közötti különbségeket használva ) és Moderna, 1 eset (placebo csoport; 12. táblázat ).

De csak mintegy négy és 31 újrafertőzésekben dokumentált globálisan, hogyan, vizsgálatok több tízezer, a medián követési idő két hónap, lehetne kilenc megerősítette covid-19 eset közül a SARS koronavírus-2 fertőzés kiinduláskor? Ez reprezentatív-e a vakcina jelentõségének jelentõségével, amint azt a CDC látszólag jóváhagyta? Vagy lehet valami más, például a covid-19 tüneteinek megelőzése, esetleg oltás vagy a tüneteket elnyomó gyógyszerek alkalmazása, és semmi köze az újrafertőzéshez?

Szükségünk van a nyers adatokra

Ezekkel a kísérletekkel kapcsolatos sok nyitott kérdés megválaszolásához hozzáférés szükséges a nyers próbaadatokhoz . De úgy tűnik, hogy jelenleg egyetlen vállalat sem osztott meg adatokat harmadik féllel.

A Pfizer azt állítja, hogy az adatokat „kérésre és felülvizsgálat alá vonja”. Ez messze megáll az adatok nyilvánosságra hozatalától, de legalább nyitva hagyja az ajtót. Hogy mennyire nyitott, nem világos, mivel a vizsgálati protokoll szerint a Pfizer csak 24 hónappal a tanulmány befejezése után kezdi elérhetővé tenni az adatokat.

A Moderna adatmegosztási nyilatkozata szerint az adatok „kérésre rendelkezésre állnak, amint a próba befejeződik. Ez valamikor 2022 közepétől későig jelent, mivel a nyomon követést 2 évre tervezik.

Nem lehet más a helyzet az Oxford / AstraZeneca vakcina esetében, amely betegszintű adatokat ígért "amikor a vizsgálat befejeződött". Az orosz Sputnik V oltóanyagról ClinicalTrials.gov bejegyzés szerint az egyes résztvevők adatait nem tervezik megosztani.

Az Európai Gyógyszerügynökség és az Health Canada azonban jóval korábban megoszthatja az engedélyezett oltások adatait. Az EMA már vállalta, hogy a „megfelelő időben” közzéteszi a Pfizer által benyújtott adatokat a weboldalán , ahogyan az Health Canada is .

Peter Doshi , a BMJ munkatársa

Versenyző érdekek: törekedtem a vakcinakísérleti protokollok nyilvános közzétételére, és nyílt leveleket írtam alá a függetlenség és átláthatóság felszólítására a covid-19 oltással kapcsolatos döntéshozatalban.

A cikk spanyol fordítása

Lábjegyzet

A cikk számításai a következők: 19% = 1 - (8 + 1594) / (162 + 1816); 29% = 1 - (8 + 1594 - 409) / (162 + 1816 - 287). A nevezőket figyelmen kívül hagytam, mivel hasonlóak a csoportok között.



  • Dear prof. Peter Doshi,

    Thank you for your thoughtful and critical review of the article by Polack et al. and the COVID-19 vaccine landscape.
    I am a surgical oncologist and not a infectious disease or vaccine expert. I have no conflicts of interest with respect to vaccines and have no particular preference for any COVID-19 vaccine.

    However, I do feel it is part of my duty as MD, PhD to help provide people with the correct information and would advice everybody to read the Polack et al. New England Journal of Medicine (NEJM) article and discuss using the vaccine with their doctors if they have any concerns.

    Having said that, it's too bad that you post your criticism here, without giving the authors a chance to reply. You can also send a letter to NEJM or directly to the authors. Now they have no way to respond to your criticism.

    First of all, it is good that everybody knows that, before an article is accepted by the NEJM, it is reviewed by multiple independent expert reviewers, who also ask difficult questions, which the authors need to answer before an editor accepts it for publication. This process is repeated by other regulatory bodies, such as FDA/EMA, before a drug is approved and reimbursed.

    Second, to give a rebuttal to your comments:
    - Yes, the suspected COVID category is an interesting group. However, it is more or less equal for both treatment arms (well balanced). This is exactly as one would expect, since a vaccine will only reduce actual proven COVID-19 infections and not that caused by other causes. In the Netherlands (where I currently live), only 13% of all circa 50.000 people tested for COVID daily actually has the disease.
    - 371 people excluded from analysis due to protocol violations. This is true, a fact, but I remind you that it is less than 1% of the study population and can therefore hardly have influenced the study outcome. This is one of the reasons we need such a large phase 3 trial before a drug can be approved for use. Moreover, one would expect these exluded people to be evenly spread across the treatment arms. I could not find that data, but I expect FDA/EMA will have received it and interrogated it.
    - Isn't it a logical consequence that 3-4 x times more people used medication to mask side effects from the vaccine. Since they were blinded to the treatment, they did not know why they were feeling worse and these type of short term side effects is a logical effect of a vaccination treatment. I do not see any harm or bias here. Many other trials (for example in cancer) allow for supporting drugs, such as paracetamol or antiemitics.
    - Does the vaccine work in people that have had COVID? Well, I don't know if we need to have these people vaccinated to be honest. If the basics of immunology apply, they should have developed antibodies against a new COVID infection, correct? You rightfully say that we have seen very little people having re-infection with COVID after having recovered from it, thus it seems rare, as one would expect on the basis of basic immunology we have learned in medical school.
    - Also, you say with a median follow-up of 2 months. Correct again, a fact. Would it be ethical to wait 5-10 years if you already see a siginificant effect on very short notice? I don't think so. Of course, the study and follow-up of individuals continues. The pharmaceutical companies have that responsibility after a provisional approval to provide long-term data to the regulatory agencies.

    Finally, I agree very much with your demand for the raw data becoming available in the public domain. This would be great in the current age of open access.

    Sincerely,
    Dr. Alexander C.J. van Akkooi, MD, PhD

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        You make some very good points, but here's the one I had problems with:
        "- 371 people excluded from analysis due to protocol violations. This is true, a fact, but I remind you that it is less than 1% of the study population and can therefore hardly have influenced the study outcome."
        The question here isn't about the overall number. The question is why there was such a huge imbalance in numbers in this group between the vaccine arm (311 subjects) vs. the placebo arm (60 subjects) in the Pfizer trial. What happened here? Why do we have over 500% more vaccinated subjects excluded because of "protocol violations"? This kind of figure cannot be due to chance, so what caused it?
        Disclosure: I'm an MSW and the last person on earth to be an antivaxxer.

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            I agree, that information does need to be shared. I can hypothesize a few things I have experienced myself in other double blind trials: for example pharmacy by accident gave placebo to a person that was randomized to vaccine. Or other violations like this. Still, all 311 would basically all need to have a positive PCR to have been able to influence the study outcoma. Again, as stated above, I do agree that it needs to be clarified. p.s. Moderna (Baden et al. NEJM) had much less protocol violations and shows a very comparable result.

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              Where is the definitive proof the vaccine prevents viral transmission and can the immunity duration be quantified? You say that anyone who has already had cov-19 may not need the vaccine. However there have been 31 documented cases of repeated covid-19 reinfection around the world recorded on the cov-19 reinfection tracker site. These cases involved different variants. So having cov-19 does not make one immune. The mean time interval between infection being 80 days (11 weeks). This makes the advice from the UK CMO Chris Whitty of a 12 week interval between vaccinations illogical as one could obtain an infection between two jabs which has already occurred in NHS workers.

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                  Yes, good question and I agree that this is important. Unfortunately, until now, people have tested for the presence of immunoglobulins / antibodies against COVID, but we know (simple immunology 101) that these go down again after an infection, but your immune system creates a memory, which should protect against re-infection. This is exactly the principle on which vaccination is based. Therefore, it is unclear if we develop long term memory against COVID. However, there is no reason to assume why we would not develop such a memory protection against re-infections.

                  Yes, there have been a handful of cases with a re-infection described until now. Considering that nearly 100.000.000 people have had a proven COVID infection (let alone the non-proven ones), this is very rare. Also, many cases of re-infection could be explained by people having concomitant immune suppressive diseases (for example HIV) or medication (for examply in transplant recipients).

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                    Well said

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                        Well said! The primary endpoint of the trial is pre-determined. If COVID-19 infection confirmed by PCR was selected to be the primary endpoint. That’s it, period!

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                          I have just spoken to a work colleague. His brother and sister in law are both doctors and just had the Pfizer (BNT162b2) over the Christmas period in the UK (first jab only). They shortly afterwards both tested positive and were symptomatic with SARS-Cov-2.

                          Does anyone know if this data being collated?

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                            Thanks so much for exposing some of the slippery statistical issues around the vaccine trials. I would add one more problem: no measure of exposure level. Specifically, adverse effects after both 1st and 2nd dose, even if mild, might have kept participants in the vaccine arm at home/less active (thus, exposed) on average a few more days than placebo recipients. Considering the short observation window after 2nd dose (just a few weeks) available so far, one cannot rule out that this difference might have had an impact on infection rate. In any instance, I think at least some gross or surrogate data reflecting the level of exposure (e.g. population size in city of residence, n° of people in household, average interactions at work, use of public transport...) should have been included in all the studies. Intensity of exposure is more important than other factors that were carefully balanced between arms.
                            As already expressed by others, more than worried about adverse effects, I am thus far not very excited about efficacy data. Plus, when we the translate this to real world scenarios effectiveness will probably be lower. Need more data.
                            Disclosures: I have no COI; am definitely all pro-vaccines, but only if worthwhile.

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                              One needs to compare the proportions of hospitalization and ICU for the suspected covid case in both groups.

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                                While I perfectly agree that we need full data release for those trials, I find it strange that he only mentions the Oxford/AZ in passing, for which much less and much more disconcerting data is published, changing after the political need and pandemic situation. For the less effective (62%) Oxford vaccine with half the number of participants (is also if vaccinated volunteers), 87% were under 55, and similar percentages were white, all healthy, and there is no data, how effective this vaccine is in over 65s. The others have a proven efficacy in older people. So, why you vaccinate over 70s with the vaccine with no data for its efficacy for that age group and make unsubstantiated claims that they are 70% protected after one dose for at least 12 weeks suggests that price, supply and logistics are the main criteria for the choice, NOT the protection of the vulnerable from severe disease or death. We need proper publication of all trials and the dosage/timing regime, which has turned out most effective.

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                                  How confident are we of the 95% efficacy that we keep hearing repeated by the media ... in light of the following quotes?

                                  From the first journal publication cited by Dr. Doshi above (https://www.nejm.org/doi/10...

                                  The findings are descriptive in nature and not based on formal statistical hypothesis testing. Safety analyses are presented as counts, percentages, and associated Clopper–Pearson 95% confidence intervals for local reactions, systemic events, and any adverse events after vaccination, according to terms in the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1, for each vaccine group.

                                  ...

                                  The final analysis uses a success boundary of 98.6% for probability of vaccine efficacy greater than 30% to compensate for the interim analysis and to control the overall type 1 error rate at 2.5%.

                                  From the second journal publication cited by Dr. Doshi above (https://www.nejm.org/doi/10...

                                  For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 vaccine is 30% or less.

                                  ...

                                  The vaccine efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that vaccine efficacy would be 30% or less.

                                  On a reading of this, I thought the authors are saying the trial was not designed to make any statistical significant pronouncement of an effective rate - such as the 95% effectiveness rate we keep hearing about....

                                  Both studies say that the only conclusion about effectiveness that can be made with confidence is that the vaccine is at least 30% effective.

                                  Yet throughout the papers they talk of a 95% confidence of the results...

                                  And throughout media we keep hearing the vaccines are 95% effective...

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                                      Thank you Peter Doshi. Finally, a serious scientist has carefully evaluated the vaccine data and discovers some serious impropiety, inadequate transparency on these Covid vaccines, and a shocking observation of reduced efficacy to only 19%. Because these vaccines were granted "emergency exemption," these studies should be fully transparent, and yet, Dr. Doshi shows that this is simply not true. Even worse is his discovery that the Pfizer vaccine's results were adjudicated by three Pfizer employees, not independent university-affiliated physicians as the Moderna vaccine was. And the fact that in the Pfizer vaccine trial, 7 subjects in the placebo and only 1 subject in the vaccine group tested positive for Covid-19 at baseline, thereby "stacking the deck."

                                      As Lucy (of "I Love Lucy" fame) was known to say to Ricky, "You've got some 'xplain' to do!"

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                                          This comment was deleted.

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                                            The PCR is "Under sensitive"? I think you meant to say "Uber sensitive" The PCR is a highly flawed test, particularly with the number of cycles used being far too high to give meaningful results. The PCR is a horrible diagnostic with nothing to true-up the results. I'm not sure how serology data would help the situation but the false positive rate of the PCR is a huge problem in perpetuating this pandemic and stoking hysteria with the current casedemic with unreliable results.

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                                                Both false positives and false negatives a huge problems with the PCR. The WHO recently tried to address this by advising labs to provide physicians with the CT of the test along with any results. The labs in the USA have refused, stating that physicians are unable to comprehend the implications of CTs. Early in 2020, the CTs were typically far lower than they are now. This is yet another way that the data for Covid-19 is so distorted that it is virtually useless.

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                                                    The supplementary information told the tests they used. They were ones from very early in the pandemic that were very flawed and had low sensitivity.

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                                                      The false positivity is very very low for the RT-PCR. It's a highly sensitive and a highly specific test. It won't detect anything other than the viral RNA. If at all falsely positive, it's likely the sample picked up the virus during handling. Or there may be false negative due to incorrect swab collection.

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                                                          PCR can find the proverbial needle in a haystack--even inventor Kary Mullis said false positives aren't really an issue, in the context of what he invented PCR for, which is research, not diagnosis. In the context of Covid-19, calling any positive test a "case" does lead to "false positives" from the standpoint of someone actually being infectious. Put bluntly, most labs are running cycle thresholds that are too high. Dr. Fauci has stated publicly that anything over 35 cycles is "just dead nucleotides, period." Despite this, labs are running anywhere between 37 and 45 cycles. Dead nucleotides can't replicate, meaning that person cannot infect others, and yet people carrying non-infectious viral debris are considered "cases"--which is central to the current hysteria.

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                                                              Dutch RIVM says otherwise after a literature study
                                                              Sensitivity between 67% and 98%
                                                              Specificity between 96% and 99,5%.
                                                              Meaning that out of eg 100.000 PCR tests up to 4000 false postives would result.

                                                              See also https://academic.oup.com/ci...
                                                              Gives the culture results of positive PCR samples with different Ct values.
                                                              Ct = 25 up to 70 % confirmed
                                                              Ct = 30 20% confirmed
                                                              Ct = 35 < 3% confirmed.

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                                                                  The tests used in the study were ones from early in the pandemic that had low sensitivity. The study also said if the participant could not get the PCR done at the study site, they could do it themselves. These were not self-administration tests.

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                                                              It was Ricky who said that to Lucy. But yes, yes, yes.

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                                                                I have a general comment/question.
                                                                How do you even test a vaccine and compare vaccinated group to placebo group in the middle of a global pandemic, with lockdowns and panic spreading media coverage all over? Doesn't all thst have impact on behavior of tested people?
                                                                Shouldn't the high (95%) efficacy be rather described as "efficacy during pandemic conditions" or the conditions doesn't matter and the same efficacy can be expected in normal situation when people return to offices from home-offices, start to travel and use public transport again, and kids go back to school again?

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                                                                    Yes, I agree, in order to fully assess the efficacy of this vaccine, the trial participants should have been unmasked and able to live "social" lives to get a true look at "return to normal" and "true infectious rate" when in a normal setting. Having the participants continue pandemic safety standards and wear masks and socially distance, does not give data on infection rate, only infection rate when masked. Also, the majority of participants were between the ages of 18-55, this age group should yield a better efficacy rate as well compared to an older, obese or sicker demographic...as holds true with the flu vaccine. Once the vaccine is administered into the broader public, one would anticipate the 95% efficacy would be reduced.

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                                                                        But in this case, impact on behavior of tested people for both placebo and vaccinated are the same, so this method is capable theoretically :mask:

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                                                                            Historically it's done on military recruits with controlled exposure of vaccinated and unvaccinated volunteers to alive virus.

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                                                                                I have heard that WHO not so long ago suggested (or appealed for) more testing of the vaccine, even on volunteers who should take a vaccine and be exposed to a virus to speed up the process.
                                                                                Not a bad idea, in my opinion, and for sure volunteers could be found.

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                                                                                  You make a good point. Also, could it be asked if there is a distinction between "prevention" and "delayal"? Pandemic conditions has plenty of wild virus going around. But what happens over 10 years? Do some extent of cases prevented this year merely get spread out to a future date?

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                                                                                    This does not really surprise me at all. I never believed the ambitious efficacy hype and claims these vaccines have. The phase III trials were never designed to demonstrate they save lives, improve health outcomes, reduce admissions. We still are in the dark on whether they can prevent transmission of the Sars-cov-2 virus, how long immunity lasts if at all and what are the short term and long term unintended adverse effects which will take up to 20 years to determine. Already there have been 9 adverse reactions to the Pfizer vaccine. Seven in US and two in UK, these included anaphylaxis, Bell's Palsy and some other issue.

                                                                                    In UK the MHRA has only granted them temporary approval for a year, not full marketing approval, under EC 174 of the Human Medicines Regulations 2012. This implies they will be withdrawn if problems emerge. In any case they have to resubmit for approval when the temporary approval expires.
                                                                                    The Oxford Astra Zeneca vaccine is a viral vector type with a gene added, effectively they are injecting a GMO. Again long term effects are unknown, what will happen if the gene codes for something other than spike protein, or the vector causes issues. Time will tell. Personally I do not fancy having either an mRNA or a GMO vaccine. A protein subunit one light be less risky.

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                                                                                      The key argument suggesting that these "suspected but unconfirmed cases" should somehow be considered in the efficacy analysis is fundamentally flawed. It is clear from the protocol that these are subjects with any of several generic symptoms (headache, fever, nausea, vomiting, sore throat, ...) whose SARS-CoV-2 PCR test was negative -- to include these in the efficacy analysis as Doshi implies is preposterous and illogical unless you think the false negative rate of the test is near 100% or you think it is reasonable to expect a SARS-CoV-2 vaccine to prevent all flu-like symptoms from any cause, SARS-CoV-2 or not.

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                                                                                          I doubt it because the pcr test wasn't systematic in all participants according to the protocol. The only systematic PCR testing is described on page 13 of the FDA report as such: . Efficacy is being assessed throughout a participant’s follow-up in the
                                                                                          study through surveillance for potential cases of COVID-19. If, at any time, a participant
                                                                                          develops acute respiratory illness, an illness visit occurs. Assessments for illness visits include a
                                                                                          nasal (midturbinate) swab, which is tested at a central laboratory using a reverse transcriptionpolymerase chain reaction (RT-PCR) test (e.g., Cepheid; FDA authorized under EUA), or othesufficiently validated nucleic acid amplification-based test (NAAT), to detect SARS-CoV-2. The central laboratory NAAT result is used for the case definition, unless it is not possible to test the
                                                                                          sample at the central laboratory. In that case, the following NAAT results are acceptable:
                                                                                          Cepheid Xpert Xpress SARS-CoV-2Roche cobas SARS-CoV-2 real-time RT-PCR test
                                                                                          (EUA200009/A001) Abbott Molecular/RealTime SARS-CoV-2 assay (EUA200023/A001). "

                                                                                          The appendix 1 on page 78 of the pfizer report says this: "Participants who developed any potential COVID-19 symptoms listed in the protocol were to
                                                                                          contact the site immediately and, if confirmed, to participate in an in-person or telehealth visit as
                                                                                          soon as possible (optimally within 3 days of symptom onset). At the visit, investigators were to
                                                                                          collect clinical information and results from local standard-of-care tests sufficient to confirm a
                                                                                          COVID-19 diagnosis.
                                                                                          Investigators were to obtain a nasal swab (mid-turbinate) for testing at a central laboratory using
                                                                                          a reverse transcription–polymerase chain reaction (RT-PCR) test (Cepheid; FDA approved under
                                                                                          EUA) to detect SARS-CoV-2. If the evaluation was conducted by telehealth, the participant was
                                                                                          to self-collect a nasal swab and ship for assessment at the central laboratory. A local nucleic acid
                                                                                          amplification test (NAAT) result was acceptable if it met protocol-specified criteria. "

                                                                                          in both cases nowhere unconfirmed case is said to be a negative test result. It could also be no test at all. Or at-home collected nasal swab from untrained people which could lead to a lot of false negative. With no more information on what constitute an unconfirmed case or the repartition of the three possible cases: no test, negative test done by a professionnal, negative test done by an untrained person at home. The assumption isn't too far fetched.

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                                                                                            You are suggesting a massive false negative rate in the PCR testing which is ludicrous. I am actually reassured about this vaccine if this is all you can do. Not impressed. And I'm a cynic...

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                                                                                                Excellent critique. Note it is NOT a refutation, it simply raises a number of questions on protocol, which I suggest are best answered! Any attempt to tut-tut them away would only raise further suspicions, and would be unworthy of the companies.

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                                                                                                    The critics on this thread are not thinking straight, in my opinion. Yes, including all suspected cases is absurd, but that gives a rough extreme-case illustration. I think people are simply misreading what Doshi is talking about. The truth is going to fall between 29% and 95%. How cases were clinically ascertained and then adjudicated can make all the difference between 95% being accurate, or the vaccine in reality being less than 50% effective. Unbinding matters here, and if you really understand it, would NOT be expected to affect both groups equally. It would serve to overestimate both safety and efficacy, especially in Pfizer's study design. Also, all that aside, we have no idea if protocols for when to do PCRs were even followed. Again, can't verify this without the data. And what financial incentives did participating clinics have or not have? That could affect testing as well.

                                                                                                    In short, determining that fate of the planet based on pharma data that they will not make public is clearly unacceptable.

                                                                                                    Things could turn out well. But there is so much resting on chance and faith that I can't believe people are so credulous.

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                                                                                                      So you are assuming a nearly 100% false negative rate for PCR test. All right.
                                                                                                      And you are assuming that, BY CHANCE, the false negative rate for PCR test in the vaccine group was higher, thus leading to a biased estimate of 95% efficacy, and, again, you are assuming that BY CHANCE a nearly identical vaccine (Moderna) estimated a nearly identical (but - again - wrong) efficacy. In your opinion, what is the likelihood that all of this happened?
                                                                                                      Just another point: if you assume that there were 3410 infections in 44000 individuals in the trial, this would translate in about 8% incidence, in about three months. Didn't you think that this should be at least somehow representative of the actual rate of infection in the general population? Do you think that these numbers can be anyhow close to reality? About 26.000.000 people in US between august and october?

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                                                                                                          EXACTLY! Either he is claiming a 100% false negative rate and a crazy proportion of participants had COVID-19 or he is claiming that it is reasonable to measure efficacy of a SARS-CoV-2 vaccine by its ability to prevent ANY symptom of fever, sore throat, nausea, vomiting, irregardless of the cause. I find his core argument about the "suspected but unconfirmed cases" to be specious and illustrate a fundamental misunderstanding of the trial.

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                                                                                                            We definitely need to dig much further into this.

                                                                                                            In the Pfizer trial, only 2% or so of the people tested positive for covid (170 out of 8000). This is a recipe for false negative results. Let me explain.

                                                                                                            Given a 2% covid sample, even if PCR is an extremely accurate test, say as high as 95% accurate for both positive and negative tests, a false negative - that is probability of someone who has covid but tested negative - will be high very given the very small percentage of people who have covid in the sample (i.e. 2%)!

                                                                                                            Doing a simple calculation, you can calculate that given a 2% covid sample size, and assuming 95% accuracy pcr test accuracy (95% both for testing negative for negative patients and positive for positive patients), the false negative rates will be 72% and false positive rates are 5%.

                                                                                                            That is, 72% of those who tested negative actually has covid!

                                                                                                            Given such a high false negative rate, Dr. Dosher concern about the suspected cases is especially worrying.

                                                                                                            In the above, Dr. Dosher calculated 19% and 29% true vaccine rates, both assuming all the suspected cases were positive.

                                                                                                            Assuming 100% of all suspected cases were true positives is probably a little too harsh an assumption.

                                                                                                            But assuming 72% of all suspected cases were positives has good statics grounding.

                                                                                                            Using that, Pfizer reported 162 covid positive cases for placebo group, 8 for vaccine group, but to that result, we need to add 72% of the suspected cases. If we do that, we get a total of 1586 cases for the placebo group, and 1161 cases for the vaccine group - for a net vaccine effective rate of 27%, a far cry from the 95% reported - also a far cry from the 50% effectiveness rate WHO requires for a vaccine to be approved...

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                                                                                                                Thank you Peter Doshi for the concern you arose. I totally agree that data transparency is important, but I am concerned that the vaccine efficacy you calculated by including suspected cases is erroneous and misleading. In that approach, you would dilute treatment effect by increasing type II error. And the vaccine efficacy will be slightly different depends on whether you use patient numbers or patient time for your denominators. Therefore, the denominators should not be ignored. One simple way you can check the robustness of the data is to calculate the vaccine efficacy by intention to treat approach, which gives you the point estimate of vaccine efficacy 81.8% ( 1- (50/21720)/(275/21728)) for Pfizer/BioNTech and 92.9% (1-(19/15120)/(269/15210)) for Moderna/NIH. I would also be delighted to hear more your review about AZ/Oxford's vaccine trial.

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                                                                                                                    It is a shame that BMJ keeps this piece published without pointing out the issues with the argumentation. It is a shame that an associate editor of BMJ publish something so deeply flawed. There is a difference between pointing out weaknesses of the study and making bizarre assumptions and calling for totally unreasonable measures. Arguing that anything barely resembling covid should be counted as covid despite evidence showing opposite is not a reasonable critique. Considering the situation we are in this is extremely irresponsible and possibly significantly harmful.

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                                                                                                                        See reply above. He doesn't assumed 100% are false negative. By looking at the protocol it is not clear what constitute an unconfirmed case. And it's definately not only negative PCR results. While the 100% figure may be too far fetched. The assumptions behind it aren't.

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                                                                                                                          It is quite striking indeed. No panic, a simple independent analysis of full data set is required before expanding vaccination programs. I personally don’t fear side effects, I fear the lack of efficacy that may provoke loosening of distancing and confinement rules.

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                                                                                                                              Could it be that mRNA vaccine produce enough antibodies to reduce viral load enough to turn the PCR test into a false negative, plus alleviate symptoms enough that the patient still has symptoms but not severe enough to need hospitalization?
                                                                                                                              If that's the case, can it still be presumed that the vaccinated person is immunized?

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                                                                                                                                  That's exactly how a vaccine works...

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                                                                                                                                      Let me be blunt. Imagine vaccine X. Ten people take the vaccine X, none ends up in a hospital or severely ill, but all ten develop very mild symptoms that may or may not be because of SARS-COV-2. So, is the efficacy of the vaccine X 100%, or 0%? And should we investigate and elaborate in detail what happened to those people, or never mention it?

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                                                                                                                                          I wasn't clear. There were so many suspected cases which, if included, would dramatically decrease efficacy from 95%. So, the trial study protocol influenced the final efficacy number. AstraZeneca had a different protocol and ended up with only 62%. Then again, if the vaccines manage to reduce the viral load enough to turn a severe case into a mild case that goes away unconfirmed, why should we care because they benefit. Anyway, the vaccines' goals were preventing severe cases, which doesn't guarantee some of the vaccinated wouldn't catch the virus and get mildly ill.

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                                                                                                                                            The 1594 symptomatic persons in the vaccinated group, testing PCR negative, will comprise the following: those who have developed antibody via vaccine administration or by or by previous Covid-19 infection or non-immunes by either, at least by the time of testing due to vaccine failure. If sufficient antibody of the neutralizing type has already developed in this group of PCR negatives, they will be immune as far as is known i.e. suppression of viral RNA by the antibody that developed will indicate vaccine efficacy in this subgroup. They will be immune by acquisition of antibody.
                                                                                                                                            The studies have not been designed to detect immunity at time zero nor to follow the groups serologically nor to differentiate vaccine induced antibody from that occurring by infection. The antibodies developed in the first group will be against the spike protein and the latter will be against other components of the virion as well.
                                                                                                                                            At least some of those 8 persons in the vaccinated group who became PCR positive may have already developed some immunity and may be expected to shed less virus.
                                                                                                                                            PS: The Pfizer group did do serological studies in the phase 1 trial and published rates of seroconversion but this was in a very small group

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                                                                                                                                              In this puzzling manuscript,
                                                                                                                                              Peter Doshi invented a new category of COVID-19 patients: the “Suspected covid-19". According to him, "this category of disease cannot be ignored simply because there was no positive PCR test result". This means, to provide an example, that I can diagnose a tuberculosis in a patient with pneumonia even it there is not evidence of Mycoplasma tuberculosis, or a Helicobacted Pylori in a belly pain althoug I do not find it.
                                                                                                                                              This is not science, this is Harry Potter's stuff.

                                                                                                                                              Arturo Tozzi
                                                                                                                                              M.D., Pediatrician, ASL Na2Nord, Italy
                                                                                                                                              phD, Computational Intelligence Lab, University of Manitoba, Canada
                                                                                                                                              Adjunct Assistant Professor in Physics, University of North Texas, USA

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                                                                                                                                                  The assumption that 100% of suspected cases are actually infected seems unprobable.

                                                                                                                                                  The probably of false negative is very low, especially in a population where the overall population is negative for the virus.

                                                                                                                                                  Given the low level of population with virus, assuming a false negative testing rate of 5%, the false negative for the suspected cases will be is in on the order of .05% (i.e. .5*.01).

                                                                                                                                                  This would result in at most 1 patient from this pool to the confirmed cases.

                                                                                                                                                  It would not change the results...

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                                                                                                                                                    It's very difficult to study a vaccine in a healthy population against a disease which does not kill 99% of a healthy population.

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                                                                                                                                                        My biggest problem with all of these vaccines trials is the same one that always happens in every drug trial: several groups are simply excluded. The average medication trial is actually much worse in this area, with every possible group that might raise any kind of confounding factor not allowed to participate. At least with these trials, seniors and people with several chronic conditions or taking other medication were automatically excluded, which is the norm. But we still don't know how these vaccines will affect immunocompromised people, because they were specifically excluded. People with autoimmune disorders weren't flat out excluded from at least some of the trials from what I can figure out, but without the raw data, there is no way to know how many of them there were, if they were more likely to have side effects, if the vaccines were as efficacious, etc. This is an issue that should not be glossed over and ignored.

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                                                                                                                                                            By your logic, only an universal vaccine for all flu-like symptoms can be considered effective. That does not make sense at all.

                                                                                                                                                            Assuming high accuacy of covid tests, suspected cases that had the symptoms but tested covid negative is by definition not covid.

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                                                                                                                                                                Except an unconfirmed case for the trial may be one of 3 things. Sick and no test returned, sick and negative test performed by a trained professional, sick and a negative test done by an untrained person at home. Since we don't have any of those numbers, the assumption isn't too far fetched.

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                                                                                                                                                                  As Doshi and some commenters have illustrated, defining what is meant by "vaccine efficacy" is not clear cut. Does this have an ethical consequence for what kind of informed consent participants are receiving?

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                                                                                                                                                                      I have raised these concerns about these cov-19 vaccines with MD in Private Eye, if some other folk could do likewise with the general media, the BBC seems to have a non critical bias when it comes to these vaccines. Could some folk contact the Sun, Mail, Times, etc and see if they can run with it too. Personally I don't see these vaccines as a cure all to get covid done by 2021. We need to see the real data sets and we need a proper cohort study. Without effective test, track and trace it will never work.

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                                                                                                                                                                          There is also misinformed and misleading anti-vaccine claims going around. It is more important than ever to have careful discernment before making any claims -- any legitimate criticisms of the vaccine trials, shortcomings pointed out, or documented side effects need to be explored and considered, but in the context of the pandemic we are in, in which the virus is spreading exponentially all over the world and leading to so much sickness and death. Specious arguments based on non-issues don't help. We need to elucidate any real issues, clarify risks and benefits and make rational healthcare choices as we are supposed to do in our evidence-based medical world.

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                                                                                                                                                                            Thank you for this summary.
                                                                                                                                                                            This is not the only thing, if you Analyse the data you will find no EFFECTIVENESS to protect against severe Covid Cases as established in the endpoints of the study protocol.

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                                                                                                                                                                              Really? In the age of widespread COMPLETELY IRRATIONAL vaccine skepticism a BMJ editor writes a highly vaccine-skeptical article. That's going to be helpful.... Skepticism for skepticism's sake is not warranted right now - you are naively(?) playing into the hands of Wakefield and Q'Anon.
                                                                                                                                                                              All your critical points are valid, but manage to shed an overly negative light on a study which foremost documents a phenomenal success in vaccine development. I'm all for your call for transparency and source data disclosure. But your main point, the presumed ineffectiveness of the vaccine to prevent "suspected unconfirmed Covid-19" is really a mosquito blown up an elephant. About a third of the 1594 "cases" in the vaccine group may just represent constitutional vaccine side effects within 7 days after vaccination. It would have been nice to know just how sick the rest of the remaining "cases" got. Quite possibly, a significant number encountered the virus but the fact is that only 2(!!!) required hospitalization and none of them had enough virus in their nose to be picked up by RT-PCR....

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                                                                                                                                                                                  And now 29 people have died in Norway which has led to caution in giving the vaccine to the 80+ age group, for whom this vaccine was most vital anyway. Try again.

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                                                                                                                                                                                      Folks are going to get the vaccine and walk around unmasked and not follow distancing rules. Accurate description of the trial result and conditions as well as proper interpretation is needed to ensure that those people are not endangering themselves and the public.

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                                                                                                                                                                                        Thank you very much for providing such critical review on the Pfizer COVID-19 vaccine clinical trial, Dr. Doshi.

                                                                                                                                                                                        I have observed that the percentage of COVID-19 positive cases is very low, 0.4% (170 out of 43,000), which is significantly lower than estimated US infection rate (1.36%, August to October, infected cases in US are about 4.5 million) during the time of clinical trial. This suggests that the number of COVID-19 positive cases (170) is likely to be under-estimated. The suspected COVID-19 cases are surely needed to have more close follow-up to find out which are true COVID-19 positive cases. Simply taking this big chunk of data out of the consideration is not scientifically proper.

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                                                                                                                                                                                            Seems to me the Moderna trial data should be made available. As they got $billions from the US government to do the trials. So the government and us and be able to demand the data.

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                                                                                                                                                                                                Its a first glance, an interesting "find", but I find it much more likely to be a red-herring.

                                                                                                                                                                                                1) n ~30,000 for the study, and 3410 cases of "suspected covid", that's >11%, over the course of 2 months of observation. That would be an incredible penetration of COVID if it were real, the estimates are that 4% of Britain is currently infected, and that's during a bigger post-christmas wave with the new strain ascendant.

                                                                                                                                                                                                2) PCR testing in the US an canada is indicated for people with potential exposure, covid like symptoms , etc. Since people infected with COVID are already shedding virus a 1-2 days before they are symptomatic, it is unlikely people with COVID-like symptoms are not being captured via swab PCR. Furthermore, the participants are part of a study and are reporting their symptoms to be monitored and swabbed.

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                                                                                                                                                                                                    Dear Dr. Doshi,
                                                                                                                                                                                                    I think your argument about potentially high levels of false negatives among the suspected covid-19 cases is fundamentally flawed. The sensitivity of the PCR tests has to be the same for both groups in the studies. Positive results indicate that, there are almost 20 times more infections in the placebo group, thus the false negatives should also follow suit. Even if what you're saying is true and there are many false negatives, that would affect both groups proportionally, keeping the efficacy at the same rate.
                                                                                                                                                                                                    Kind Regards,
                                                                                                                                                                                                    Chris Chur

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                                                                                                                                                                                                        The original study protocol sets the threshold for a PCR test as “acute respiratory illness”, which would seem to be an appropriate one because that’s what hospitalises and kills people.

                                                                                                                                                                                                        “Efficacy will be assessed throughout a participant’s involvement in the study through surveillance for potential cases of COVID-19. If, at any time, a participant develops acute respiratory illness (see Section 8.13), for the purposes of the study he or she will be considered to potentially have COVID-19 illness. In this circumstance, the participant should contact the site, an in-person or telehealth visit should occur, and assessments should be conducted as specified in the SoA. The assessments will include a nasal (midturbinate) swab, which will be tested at a central laboratory using a reverse transcription–polymerase chain reaction (RT-PCR) test (Cepheid; FDA approved under EUA), or other equivalent nucleic acid amplification–based test (ie, NAAT), to detect SARS-CoV-2. “ (p.55)

                                                                                                                                                                                                        https://pfe-pfizercom-d8-pr...

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                                                                                                                                                                                                            Wouldn't this present itself also as a problem, in that trial participants were to self report if they had symptoms, as opposed to mandatory follow up testing weekly or bi-monthly to see if they were infected? Especially when we know that possibly up to 40% of people may be asymptomatic?

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                                                                                                                                                                                                                This limitation in the design means only symptomatic disease was tested -- not asymptomatic. But the fact that it was double blind and there was such a strong discrepancy in confirmed cases (162:8) is strong evidence of efficacy, but more studies are necessary to assess how much of this benefit extends to asymptomatic disease or reduction of transmission.

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                                                                                                                                                                                                              Do you really think it is appropriate to assume that PCR tests have 100% false negative rate? Have you considered how this vastly exaggerated numbers will effect public trust in vaccines? I understand it is entirely appropriate to demand more data sharing but what you eventually achieved is to provide more false evidence to anti-vaxxers.

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                                                                                                                                                                                                                  Your assumption is as false as his. He is not claiming 100% false positive. He is claiming that without access to raw data we can assume a lout of people are not included in the end point. We don't know how many people who experienced symptoms got tested, how many received a negative result based on a test properly done by a trained professionnal, how many got a negative result based on a test done at home by an untrained individual with a high likelyhood of false negative.

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                                                                                                                                                                                                                      Exactly! He is either claiming 100% FNR and that a ridiculous % of the participants were indeed SARS-CoV-2 infected or he is arguing that it is reasonable to expect efficacy for a SARS-CoV-2 vaccine to prevent any symptoms such as fever, nausea, vomiting, sore throat, etc. from any cause, even if not due to SARS-CoV-2. Preposterous and specious argument.

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                                                                                                                                                                                                                        Could you analyze the difference between the positive effects of placebo
                                                                                                                                                                                                                        (21,278 disease-free from 21,566 observed) against the positive
                                                                                                                                                                                                                        effects of vaccine (21,712 disease-free from 21,720 observed) ? This
                                                                                                                                                                                                                        speaks about the pertinence of vaccinal health politics for the society.

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                                                                                                                                                                                                                            - Why were both of these trials "observer-blinded", and not double-blinded? There is no explanation in the texts. There are no obvious descriptions of the nature of interactions between patients and clinicians. By "observer"-blinded, does that mean the patients were unblinded?
                                                                                                                                                                                                                            - Whether they were or not, unblinding of both parties should be anticipated. Unblinding could have many consequences. For example, does a clinician get lazy about PCR testing if they think the symptoms are due to a recent injection that wasn't a placebo? Does a patient even bother consulting a clinician if they think their symptoms are from a vaccine? And could the exact opposites be true if patients/clinicians suspect they got a placebo? Could "testing fatigue" occur? By that, I mean could a negative PCR following vaccine-caused symptoms lead to less likelihood of running a PCR 2 weeks later when real disease symptoms emerge?
                                                                                                                                                                                                                            - Why was testing left up to clinician judgement? Do the clinicians have any ties to the pharmaceutical companies?
                                                                                                                                                                                                                            - There is not enough info on dropouts. What a patient says and what an observer records are not always the same thing. Can we trust that so many dropouts were for the innocuous reason of "withdrawing consent"? Are cases of illness or reactions being unreported in some dropouts? It is common that when patients abandon a treatment, they simply don't follow up
                                                                                                                                                                                                                            - The Moderna study cited 30 severe cases occurring from 14 days after the second dose. They had more than 14,000 people in each group. This is at odds with the Pfizer data which says only 5 total cases occurred from 7 days after second dose. This means Pfizer had longer to observe cases, plus their group size was nearly 22,000. This discrepancy needs explaining. Is this just random chance, or something else? Extrapolating from Moderna's count, under simple expectation, one would expect more like 70 cases to be reported by Pfizer, not five.
                                                                                                                                                                                                                            - What is going to happen months or years down the line if boosters are needed? Could pathogenic priming start becoming apparent at such a later date?
                                                                                                                                                                                                                            - In the Moderna supplements, there seems like a possible signal for grade 4 events, but what such events are is not clearly defined.
                                                                                                                                                                                                                            - Will we be promoting new vaccines to people who have already had COVID but don't know it?

                                                                                                                                                                                                                            So to recap...We have clinical trials with subjective outcomes, patients and clinicians who are likely unblinded, outcome measures that aren't the ones we really care about, and in any case the vast majority of suspected cases are excluded from primary analysis, and to top it off the raw data is not available? Personally, it is hard for me to fathom that the existing published studies at 2 months are of any value whatsoever.

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                                                                                                                                                                                                                                Actually the study of Pfizer was double blinded! "A randomized, double-blind study of an mRNA vaccine encoding the SARS-CoV-2 spike protein. 43,548 participants ≥16 years old were assigned to receive the vaccine or placebo by intramuscular injection on day 0 and day 21. Participants were followed for safety and for the development of symptomatic Covid-19 for a median of 2 months."

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                                                                                                                                                                                                                                    All excellent questions. In fact as Doshi mentions, a blinded study is not possible because vaccines have side effects that distinguish them from placebo.

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                                                                                                                                                                                                                                        That is one point I agree with, but still does not change the efficacy results much. One would have to suppose that the side effects (note that most side effects have prevalence <5% and are not specific to the vaccines) were sufficient to unblind, and that those "unblinded" then did not report symptoms of COVID-19 as instructed under the protocol, and that there were enough of these to produce as lopsided a ratio of symptomatic cases in placebo:vaccine as 162:8. This is highly implausible. While a potential source of bias, there is no way for this to explain away the stellar efficacy results.

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                                                                                                                                                                                                                                          Had some more time to dig through the protocols. Corrections/clarifications:

                                                                                                                                                                                                                                          - Both protocols do suggest patients were blinded. Pfizer's says: "the study intervention syringes will be administered in a manner that prevents the study participants from identifying the study intervention type based on its appearance." Moderna's states, "The investigator, study staff, study participants, site monitors, and Sponsor personnel (or its designees) will be blinded to the IP administered until study end, with the following exceptions:" So I suppose the misleading term "observer-blinded" used in NEJM is meant to imply that some non-observer personal were unblinded.
                                                                                                                                                                                                                                          - We might take a lesson from antidepressants, where pattern of side effects and other factors may lead to rampant unblinding (doi: 10.1016/0165-1781(86)90094-6)
                                                                                                                                                                                                                                          - The Pzifer protocol looks as if patients were to initiate contact with clinicians of their own volition. Patient unblinding could definitely risk affecting patient behavior here. Moderna's protocol looks more robust in this regard. Patients filled out a e-diary every 2 days, were called if they skipped this, and were solicited weekly regarding symptoms. Though following the 7 days after vaccination, PCR was left to clinician judgement. Though they also took swabs shortly before each shot to offset this last concern.
                                                                                                                                                                                                                                          - Though even if a robust protocol is described, we have no way of telling how strictly criteria for doing PCRs were followed/biased without the raw data.
                                                                                                                                                                                                                                          - Moderna's supplements do define Grade 4 AE's for the most part as things requiring ER visit or hospitalization.

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                                                                                                                                                                                                                                            You raise some significant concerns overall, and in particular in relation to blinding.

                                                                                                                                                                                                                                            However, you seem to have missed the fact that according to bottom of page 32 of the protocol at https://pfe-pfizercom-d8-pr... it is clear that the person administering the vaccine is UNBLINDED.

                                                                                                                                                                                                                                            Having designed and run clinical trials, I'd regard this as a major weakness. I'd certainly want more transparency about training and recording around the administration process.

                                                                                                                                                                                                                                            This is all the more important given that there were 20 x as many subjects with symptoms who underwent PCR testing than didn't. A relatively small "nudge" affecting propensity to go for testing would have pretty profound implications for the validity of the trial.

                                                                                                                                                                                                                                            The final point to make is that the recent WHO bulletin re PCR testing at https://www.who.int/news/it... cannot be ignored in relation to these trials.

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                                                                                                                                                                                                                                                Are those "suspected Covid-19" cases tested for RT-PCR swabs ?

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                                                                                                                                                                                                                                                  As these were just EUAs (Emergency Use Authorizations) and not FDA approvals, the blog and comments will help the companies to submit the right data to the FDA for approval. Clinical trials are full of confounding factors, but some real life data has just been reported at https://www.bbc.com/future/...
                                                                                                                                                                                                                                                  The truth is probably somewhere in between.

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                                                                                                                                                                                                                                                      Thanks Peter Doshi and all the follow up discussion participants. Good to see. Certainly we need more data and discussion.
                                                                                                                                                                                                                                                      Three questions: Do we need independent trialing and assessments?
                                                                                                                                                                                                                                                      Should Sanger Sequencing be the standard test for research inc vaccines?
                                                                                                                                                                                                                                                      Vaccine trial end points: Why no discussion of viral replication when vaccinated? Failure here could be a significant (biggest?) danger. Put simply: doesn't using the perfect "petri dish" mean all mutations are tested against the control in vivo? The randomisation and depth of this "trail" is frightening. How many Patient Zeros do we need?

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                                                                                                                                                                                                                                                          In my view, the opinion by Peter Doshi is based on the assumption that the average reader has perfectly memorised all the numerical results of the Pfizer trial. As a result, owing to the lack of more detailed explanations, a real understanding of this opinion is not straightforward for the average reader and also for the specialised reader with an average expertise. In particular, to make the explanatory footnote more understandable, the absolute numbers that appear in the equation should be recalled and explained without the need to reanalyse the full text of the trial.
                                                                                                                                                                                                                                                          Andrea Messori
                                                                                                                                                                                                                                                          Firenze (Italy)

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                                                                                                                                                                                                                                                              Hi Peter, I cannot find "3410 total cases of suspected, but unconfirmed covid-19" in the report. Can you help? Also, what is the basis of not counting these cases, & is there info about how they took the PCR tests?

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                                                                                                                                                                                                                                                                  They are from the top two paragraphs of page 42 of the FDA report. But looking in the protocol, it seems clear that these "suspected but unconfirmed covid-19 cases" are just those who reported any generic symptom specified in Section 8.13 on page 88 of the protocol document that indicated a visit to give a SARS-CoV-2 PCR test, whose PCR test was negative. Doshi's article suggests these are covid-19 cases that are somehow not reported in the efficacy analysis, when in fact it seems clear from the protocol these are just the people who reported symptoms but had negative PCR tests. His suggestion that these should be included in the efficacy analysis is puzzling to say the least, unless one thinks that it is reasonable to expect a SARS-CoV-2 vaccine to prevent all symptoms such as fever, headache, nausea, vomiting, sore throat etc. from any cause.

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                                                                                                                                                                                                                                                                    I don't understand something: Did the "suspected cases" test negative? Or was there no test at all? If they were not tested, why weren't they?
                                                                                                                                                                                                                                                                    If they tested negative then not much to worry about

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                                                                                                                                                                                                                                                                        They were all tested.

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                                                                                                                                                                                                                                                                            That is just plain false assumption. The protocol states the only systematic testing is on people with respiratory problems. Hence the call for raw data. The nature of testing is also important. What's the proportion of test done by trained professionnals and the proportion of tests done by people at home and shipped to a laboratory. With no data on these three points the criticism is legitimate.

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                                                                                                                                                                                                                                                                            Wow. This expose should be on the front page of every news outlet yet no one is covering this. Instead, we get a week long bashing of the Chinese vaccines. Interesting.

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                                                                                                                                                                                                                                                                                In the link provided you can find the following sentence:
                                                                                                                                                                                                                                                                                "not PCR-
                                                                                                                                                                                                                                                                                confirmed were not recorded as adverse events unless they met regulatory criteria for
                                                                                                                                                                                                                                                                                seriousness. Two serious cases of suspected but unconfirmed COVID-19 were reported"

                                                                                                                                                                                                                                                                                This seems an explanation of the doubts expressed here, isn't It?

                                                                                                                                                                                                                                                                                I mean, if only two suspected had severe symptoms, this means that hospitals will be protected from flooding, and people will be protected from severe symptoms, this is not enough?

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                                                                                                                                                                                                                                                                                    did they follow up the participants, with PCR test every 3/4 days for both the groups for the entire length of the study ? If not, why ?

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                                                                                                                                                                                                                                                                                      So the verum group had 222 less cases of suspected COVID and 154 less cases of suspected and pcr-confirmed COVID than in the control group. As the vaccination only reduces the number of cases of people with influenza like symptoms (aka suspected COVID) by reducing the relative small number of COVID cases among them, it is this difference that needs to be explained.

                                                                                                                                                                                                                                                                                      This difference more than accounts for false negatives in the PCR test. Parts of the difference could also be explained by an "un-blinding" caused by the more frequent side effects of the verum : those who had an reaction to the injection were more likely to believe to be protected from COVID and thus less likely to worry about and report very mild symptoms.

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                                                                                                                                                                                                                                                                                        Clarification: The last paragraph refers to Clinical Study Reports (CSRs), not IPD. In contrast to the FDA, EMA do not request or review IPD from manufacturers, so EMA cannot provide access to IPD. EMA do however provide access to CSRs.

                                                                                                                                                                                                                                                                                        Footnote: FDA provides access to neither IPD nor CSRs.

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                                                                                                                                                                                                                                                                                            Correct. The author of this opinion does not have all of the information and his analysis, while plausible, is speculative in the absence of more evidence.

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                                                                                                                                                                                                                                                                                                That is exactly his point. The data should be made public PRIOR to HCPs making decisions about whether or not to recommend the vaccines to patients. Instead, it is not going to be made public until after it is expected that the entire population of the globe is immunized with them.

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                                                                                                                                                                                                                                                                                                    Absence of data more like. In all of these vaccines, Pfizer, Moderna, Astra Zeneca, the trials were not designed to show they save lives, improve health outcomes, we still do not know if they prevent transmission and they cannot quantify the duration of immunity if any. There have been 31 cases of cov-19 repeated reinfection documented in the literature and recorded on the cov-19 reinfection tracker site suggesting repeat cov-19 infections likely and do not provide immunity for other variants. The average time between infections was 11 weeks inside the 12 week suggested interval by Chris Whitty!

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                                                                                                                                                                                                                                                                                                        31 cases of COVID-19 reinfection out of 10s of millions of initial infection does not seem like something to get alarmed about. That is a much higher level of protection that that claimed by any of the vaccines approved so far

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                                                                                                                                                                                                                                                                                                      And hopefully we will soon see the start of a large PhIII trial of intranasal application of a vector-based vaccines. There is some really encouraging data available regarding mucosal immunity from studies in hamsters and non-human primates. Only this will at some point in time bring us herdimmunity, thats what we need.

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                                                                                                                                                                                                                                                                                                          In Israel the majority of the vulnerable population has already received the first dose. With beginning of February cases will remain high, but deaths will drop to close to 0, also after opening up the economy. It isn't exactly how it should be done, but given the situation we are in the benefits outweighed the risks and emergency approval was definitely the way to go. The highly similar outcome of the Moderna trial additionally adds confidence about the efficacy of the vaccines.