Beartrap is right. Any significant amendment or update to the SAP, particularly the last one for unblind would be sent to the regulator for them to comment if they wish to do so.
You don't want your BLA laughed out of court in five minutes, so you run the last revision of the SAP past the regulator.

Thanks Lykiri. I'd fallen behind with new Advent recruitment.
I see that the lead author is still currently working as a scientist for the MHRA.
Which I find rather interesting.

I expect Sawston licensing anytime soon.

Regards.

Hi Lykiri.
Any luck tracking down who the hell these authors are (apart from Mike Scott)...?

New names.
All supposed to be from Advent..

If they are alive their files aren't complete.
Nor are they if they await IDH mutation status test results.
Which might be most of them.

But, there might be an argument for softlocking or perhaps even hardlocking, even without full IDH results.
IDH results are really not much more than addendum statistics after all.
Now you could ask why didn't they do the IDH testing back in the day? Well they didn't even know about it in the early years.
And it's not a biomarker that's been in the protocol or any version of the SAP. The chances are that a regulator asked for it after the last version of the SAP was submitted for regulator comments.

Just my opinion.

Why do you keep mentioning politics?

Well you may not think he is on the right track at all. And he is not a physician. And I bet he's left out loads of input factors that I would include.
Most obviously treatment protocol, which varies considerably from country to country! Countries that mechanically vent patients before last resort will probably have excess deaths.
I don't really place any great store on Chinese stats because they are perhaps even more dubious than the dubious stats from many Western countries. China is a bit of a closed book for me.
We've no real idea if the virus is widely abroad beyond Wuhan.

Surely Japan, having an old population, and low mortality is in support of his thesis. More of their population appear to possess the 'dark matter' that he talks about.
(Bit of a silly, unhelpful term, mind you.)
But apart from his view that some populations have greater inherent / innate immunity, the analogy of a firework that burns brightly until it runs out of fuel is not a bad one.
Being or becoming non-susceptible is the important thing.

And if you're young and or have a healthy immune system, you start off with innate immunity or at least relative immunity. Or you do become infected, but have a healthy T cell response, which eradicates the virus without necessarily any neutralizing antibodies being produced.
Or you have an infection and do produce antibodies.
Or you have some sort of pre-existing genetic immunity or at least resistance.
All these groups put together represent the collective immune group. As this group increases, the pool of susceptible individuals gets smaller.
NYC experienced the virus when the flame of the firework had just been ignited. Which is not out of keeping with his view.

The Somali immigrant population in Sweden have 5 times the death rate compared to the rest of the country. But why that should be is not clear. It could be genetics. It could be that Somali immigrants who don't understand Swedish, weren't able to take on board the health messages as well. It could be economic disparity, perhaps reflected in poorer neighborhoods, with a more densely packed population.

So I do think the Friston viewpoint has some limitations.
And computer modellers often don't understand the real world.
It's a bit like statisticians don't understand medicine. And physicians make bad investors (not all of them). It's rare for someone to understand wider issues outside of their own narrow professional sphere.
There must be very good reasons why a country like India has exceedingly low mortaliy. Huge population, huge density in the cities, a decent medical system, but by no means cutting edge, and potential capacity issues. Poor sanitation in many city areas. People don't always have the facility to wash their hands every 5 mins. My hypothesis is that much of their population already had some form of pool immunity. And that is likely to be genetic due to pathogen exposure over several generations.
Plus they use HCQ!
And countries that live with malaria have low rates of Covid deaths. And malaria-free countries have high rates.

But the firework running out of fuel is not a bad metaphor, imo.
Pick any European country, such as Germany, Belgium, Italy, Spain, Sweden and look at the graphs of declining deaths and cases.
This rapid peaking followed by a steady decline happens almost regardless of whether there is a lockdown regime, how strict it is, or how early it is relaxed.
And the steady decline represents a declining susceptible population.
Bluetooth apps lose any real sense, when you are halfway down the declining slope.
The only effect they have is to maintain the size of the susceptible population!

Mainly opinion.

Obviously depending on geographical location, I would try and get a consultation with LL or someone of her calibre.
A new MRI with a fresh interpretation would be beneficial. Low grade tumors often become high grade eventually.
Or it may be possible to get the latest few MRI images sent to UCLA or similar to get a second opinion, including another view on operability.
Yep, that's what I think I'd do. Get the scans sent to a top centre to get a fresh opinion.
I think that would be sensible even if there is no way to get DCVaxL.

NCT00068510 shows that DCVax-L can most definitely be effective for rGBM in human patients, not mice.
And so indeed do Kat and Kristyn's Dad.

Though it may be somewhat dependent on when the vaccine was created and whether it was produced from the original tumor or from the recurrent tumor.
It's most likely to be effective if it is produced from the newly resected recurrent tumor, and used immediately, without intermediate chemorad re-challenge.
It's anyone's guess how effective L can be if it was made from the original nd resected tumor, but not used until recurrence. In the interim the SOC chemorad will have accelerated a process of tumor mutation, so the tumor will be genetically different from the original resected one that was used to manufacture the vaccine.
The tumor will actually mutate even in the absence of therapy.

And that is why nobody really knows how much benefit crossover patients will derive.

https://clinicaltrials.gov/ct2/show/NCT00068510

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071163/

(View Table 1.)

The really harmful thing about this fiction piece on HCQ is that almost overnight, HCQ will have become unavailable to millions of Covid victims as a result. It was safe (even safer than old chloroquine), dirt cheap (every country could afford to use it), and I believe, effective at preventing mild to moderate symptoms escalating to severe.
Even our own Iwasadiver reported that his facility had stopped using it due to this paper (iirc). The paper was the culmination of a campaign of disinformation over the last month.

The NIH reported back in 2005 that Chloroquine was effective for the SARS virus and safe. So Fauci knew.
"Chloroquine is a potent inhibitor of SARS coronavirus infection and spread"

They also suggested that CQ also reduced infectivity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

But in the last few weeks it has suddenly become unsafe and not effective....


Contrast that with the unapproved Remdesivir that seems to be getting the green light everywhere, with projections of revenue by 2022 of $7.7B...
And it is being talked up by Fauci (and the other AF). It failed a trial in China, the results were put in error by WHO, until Gilead got them taken down. And now they're fast tracking it from the US trial (which had a pretty meaningless endpoint) by ending it early before comprehensive data is available. But that sham trial would take ages to go into.

You may be aware that NEJM also published a Surgisphere paper on ACE inhibitors. That is also now widely viewed as fiction.
So now both the Lancet and the NEJM have had to publish 'expressions of concern' about the respective papers.
Both were supposed to have been peer reviewed..
Your comment; 'Blows a big hole in the confidence we should have in the peer-review process, if it wasn’t already shot.'
It was shot a long time back..
A musket ball, iirc (it was a long time ago...)

“Finding truth these days is as difficult as finding a virgin in California.”
Virgin on impossible, I would say..
(Not intended as a serious slur on California girls!)

There is one guy who is actually trying to wake up the US public.
Del Bigtree. He is too well known to be silenced, and doesn't have a medical career that can be destroyed.



I recommend all his videos from last couple of weeks.
(In one, he neatly points out that the most commonly used flu vaccine in the US has a higher mortality rate than Covid!)


Finally, as I've been saying a while now, in a video from today Prof Karl Friston takes a view that in many populations across the world, up to 80% are simply not susceptible to Covid.



Regards.

Why is Scotty?

Hi JD. Are you far off break even yet?

Think about the PFS endpoint.

Thanks, pgsd. That's a useful list.

My eye was drawn to:-

"the Committee for Medicinal Products for Human Use (CHMP) recently adopted a negative opinion on extending the current indication of bevacizumab (Avastin) to include use in patients with recurrent glioblastoma"

CHMP is the EMA.

I don't know. My horror at this is entirely non party political, I should say. Though there has to be a paymaster somewhere, just like with Phase V.

Perhaps Danielle Steel wrote it...
Probably not. She has written 179 pieces of fiction.

These guys have only written three, that I know of.

This is the list of clinicians, medical researchers, statisticians, and ethicists from across the world, who signed the letter of concern.
And you don't get this kind of mass signing within a few days of the paper being published, unless a paper is obviously fake:-

List of Signatories:-
Dr James Watson (Statistician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)1Professor Amanda Adler (Triallist & Clinician,Director of the Diabetes Trials Unit,University of Oxford,UK)Dr Ambrose Agweyu (Medical researcher, KEMRI-Wellcome Trust Research Programme, Kenya)Professor Dani Prieto-Alhambra(Epidemiologist,University of Oxford, UK)Dr Ravi Amaravadi (Researcher,University of Pennsylvania, USA)Professor Juan-Manuel Anaya(Clinician, Universidad del Rosario, Colombia)Professor Nicholas Anstey (Clinician, Menzies School of Health Research, Australia)ProfessorYaseen Arabi (Clinician and researcher, King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia)Dr Elizabeth Ashley (Clinician, Director of the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Laos) Professor Michael Avidan (Clinician, WashingtonUniversity in St Louis, USA)Professor Kevin Baird (Researcher, Head of the Eijkman-Oxford Clinical Research Unit, Indonesia)Professor Francois Balloux (Researcher, Director of the UCL Genetics Institute, UK)Dr Clifford George Banda (Clinician, University of Cape Town, South Africa) Dr Edwine Barasa(Health economist, KEMRI-Wellcome Trust Research Programme, Kenya) Dr Ruanne Barnabas (Physician Scientist, University of Washington, USA)Professor Karen Barnes (Clinical Pharmacology, University of Cape Town, South Africa)Professor Enrico Bucci(Systems Biologist,Temple University, USA)Professor Buddha Basnyat (Clinician, Head of the Oxford University Clinical Research Unit -Nepal, Nepal)Professor Philip Bejon (Medical researcher, Director ofthe KEMRI-Wellcome Trust Research Programme, Kenya)Professor Mohammad Asim Beg (Clinician/Researcher, Aga Khan University,Pakistan)Prof. Linda-Gail Bekker(Clinician, University of Cape Town, South Africa)Professor Leïla Belkhir(Clinician, UniversitéCatholique de Louvain, Belgium)Mr Mostapha Benhenda (Data scientist, Melwy and COVIND Covid-19 Individual Patient Data Consortium, France)Professor Marc Bonten(Clinician/Researcher,UniversityMedical Center Utrecht, The Netherlands)Professor Bjug Borgundvaag(Clinician, Directorof the Schwartz/Reisman Emergency Medicine Institute, Canada)Professor Emmanuel Bottieau (Clinician, Institute of Tropical Medicine, Antwerp, Belgium)Professor David Boulware (Researcher & Triallist, University of Minnesota,USA)Professor Anders Björkman (Clinician, Karolinska Insitutet, Sweden)Dr Sabine Braat (Statistician, University of Melbourne, Australia)Professor Frank Brunkhorst(Clinician& Directorof theCenter of Clinical Studies, Jena University Hospital, Germany)Professor James Brophy (Clinician/Epidemiologist, McGill University, Canada)Professor Caroline Buckee (Epidemiologist, HarvardTH Chan School of Public Health, USA)Dr James Callery(Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Todd Campbell Lee (Researcher, McGill University, Canada)Professor Adrienne Chan, MD MPH FRCPC (Researcher, University of Toronto, Canada)Professor John Carlin (Statistician, University of Melbourne & Murdoch Children’s Research Institute, Australia)Dr Nomathemba Chandiwana (Research Clinician, University of the Witwatersrand, South Africa)Dr Arjun Chandna (Clinician, Cambodia Oxford Medical Research Unit, Cambodia)Professor PhaikYeong Cheah (Ethicist/Pharmacist, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Allen Cheng (Clinician, Monash University, Australia)Professor Ivy Cheng (Clinician/Researcher, University of Toronto, Canada)ProfessorKesinee Chotivanich(Researcher, Mahidol University, Thailand)Professor Leonid Churilov (Statistician, University of Melbourne, Australia)Professor Ben Cooper (Epidemiologist, University of Oxford, UK)Dr Cintia Cruz (PaediatricianMahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Bart Currie (Director, HOT NORTH, Menzies School of Health Research, Australia)Professor Joshua Davis (Clinician, President of the Australasian Society for Infectious Diseases, Australia)ProfessorJeremy Day (Clinician, Oxford University Clinical Research Unit, Vietnam)Professor Nicholas Day (Clinician,Director of the Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Hakim-Moulay Dehbi (Statistician, University College London, UK)ProfessorJustin Denholm (Clinician, Researcher, Ethicist, Doherty Institute, Australia)DrLennie Derde (Intensivist/Researcher, University Medical Center Utrecht, The Netherlands)Professor Keertan Dheda(Clinician/Researcher, University of Cape Town,& Groote Schuur Hospital, South Africa)Dr Mehul Dhorda (Clinical Researcher, Mahidol Oxford Tropical Medicine Research Unit, Thailand) Professor Annane Djillali (Dean of the School of Medicine, Simone Veil Université,France)Professor Arjen Dondorp (Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Joseph Doyle (Clinician, Monash University and Burnet Institute, Australia)Professor Emeritus Jean Dupouy-Camet (Former president of the European Federation of Parasitologists, Paris University, France)Dr Anthony Etyang (Medical Researcher, KEMRI-Wellcome Trust Research Programme, Kenya)Dr Caterina Fanello (Epidemiologist, University of Oxford, UK)ProfessorNeil Ferguson (Epidemiologist, Imperial College London, UK)Dr Ricard Ferrer(Head of Department of Intensive Care, Hospital Universitari Vall d’Hebron, Spain)Professor Andrew Forbes (Statistician, Monash University, Melbourne, Australia)Professor Oumar Gaye (Clinical Researcher, University Cheikh Anta Diop, Senegal)Dr Ronald Geskus (Head of Statistics at theOxford University Clinical Research Unit, Vietnam, Dr Mellie Gilder (Clinician/Researcher, Chiang Mai University, Thailand)Professor Emeritus Richard Gill(Mathematician/Statistician, Former President of Dutch Statistical Society, The Netherlands)Professor Dave Glidden (Biostatistics, University of California, USA)Professor Azra Ghani (Epidemiologist, Imperial College London, UK)Prof PhilippeGuerin (Medical researcher, University of Oxford, UK)Dr. Raph Hamers (Clinician/Triallist, Eijkman-OxfordClinical Research Unit, Indonesia)Dr Rashan Haniffa (Clinician/Researcher, NICST, Sri Lanka)Professor Stephane Heritier(Statistician, Monash University, Australia)Dr Thomas Hiemstra(Triallist, University of Cambridge, UK)Dr. Risa Hoffman (Clinician/Clinical Researcher, University of California, USA)Professor Peter Horby (Clinical Researcher, Centre for Tropical Medicine and Global Health, University of Oxford)Dr Sybil Hosek(Clinical Researcher, Cook County Health, USA)DrJens-Ulrik Jensen (Clinician/Triallist, University of Copenhagen, Denmark)Dr Hilary Johnstone (Clinical Research Physician, Independent)Professor Christine Johnston (Clinical Researcher, University of Washington School of Medicine, USA)Professor Peter Jüni(Directorof the Applied Health Research Centre, University of Toronto, Canada)Professor Kevin Kain (Clinical Researcher, University of Toronto, Canada)Dr Sharon Kaur (Ethicist, University of Malaya, Malaysia)Dr Evelyne Kestelyn (Head of Clinical Trials, Oxford University Clinical Research Unit, Vietnam)Dr Patricia Kissinger(Clinical Researcher, Tulane University, USA)Professor Megan Landes (Clinician/Researcher, University of Toronto, Canada)Dr Tan Le Van (Medical Researcher,Oxford University Clinical Research Unit, Vietnam)ProfessorKatherine Lee (Statistician, University of Melbourne, Australia)Professor Laurence Lovat (Clinical Director of WellcomeEPSRC Centre for Interventional & Surgical Sciences, UCL, UK)Dr Nsobya Samuel Lubwama (Researcher, Makerere University College of Health Sciences,Uganda)Professor Kathryn Maitland (Clinician, Imperial College London/KEMRI Wellcome Trust Programme, Kenya)Dr Julie Marsh (Statistician, Telethon Kids Institute, Australia)Professor John Marshall (Clinician/Researcher,University of Toronto, Canada)ProfessorGary Maartens (Clinician, University of Cape Town, South Africa)DR Ignacio Martin-Loeches(Clinician, Trinity College Dublin, Ireland)Professor Richard Maude (Clinician/Epidemiologist, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Mayfong Mayxay (Clinician/Researcher, Lao-Oxford-Mahosot Hospital-WellcomeTrust Research Unit, Laos)DrColin McArthur (Clinician/Triallist, Auckland City Hospital and Monash University)DrEmily McDonald (Clinician/Researcher, McGill University Health Center, Canada)ProfessorRose McGready(Clinician/Researcher, Shoklo Malaria Research Unit, Thailand)Dr Alistair McLean (Medical researcher, University of Oxford, UK)Professor Shelley McLeod (Clinical Epidemiologist, University of Toronto, Canada)Dr John McKinnon (Clinician/Researcher, Henry Ford Health System, USA)DrBryan McVerry (Medical researcher, University of Pittsburgh, USA)Laura Merson (Clinical researcher, University of Oxford, UK)Professor Clara Menendez (Clinical Researcher, Barcelona University, Spain)Professor William Meurer (Clinician/Medical researcher, University of Michigan, USA)Professor Ramani Moonesinghe (Clinician researcher, UniversityCollege London, UK)Dr Kerryn Moore (Epidemiologist, London School of Hygiene and Tropical Medicine, UK)Dr Rephaim Mpofu (Clinician, University of Cape Town, South Africa) Dr Mavuto Mukaka (Statistician, Mahidol Oxford Tropical Medicine Research Unit, Thailand) Dr Srinivas Murthy (Clinical Researcher, University of British Columbia, Canada)Professor Kim Mulholland (Clinician, London School of Hygiene &Tropical Medicine, UK)Professor Daniel Neafsey (Researcher, Harvard T.H. Chan School of Public Health, USA)Professor Paul Newton (Clinician, University Oxford, UK)Professor Alistair Nichol (Clinician Researcher, University College Dublin, Ireland,&Monash University, Australia)Professor Francois Nosten (Clinician, Director of the ShokloMalaria Research Unit, Thailand)Dr Matthew O’Sullivan (Clinician, Westmead Hospital & University of Sydney, Australia)Professor Piero Olliaro (Clinical Researcher, University of Oxford, UK)DrWilliamO’Neill(Clinician/Researcher, Henry Ford Health System, USA)ProfessorMarie Onyamboko (Clinical researcher, Kinshasa School of Public Health, DRC)Dr Marcin Osuchowski (Medical researcher, Ludwig Boltzmann Institute, Austria)Professor Catherine Orrell (Clinical Pharmacologist, University of Cape Town, South Africa)ProfessorJean Bosco Ouedraogo (Medical Researcher, WWARN, Burkina Faso)Dr Temitope Oyedele (Clinician, Cook County Health, USA)Dr Michael Paasche-Orlow(Clinical Researcher, Boston University, USAElaine Pascoe (Statistician, University of Queensland, Australia)Professor Michael Parker (Director of The Wellcome Centre for Ethics and Humanities,The Ethox Centre, University of Oxford,UK)Professor David Paterson (Clinician, Director, UQ Centre for Clinical Research, Australia)Dr Kajaal Patel (Paediatrician, Cambodia Oxford Medical Research Unit, Cambodia)Tom Parke (Statistician, Berry Consultants, UK)Professor Philippe Parola (Researcher, Aix-Marseille University, France)Professor Weerapong Phumratanaprapin(Deputy Dean of the Faculty of Tropical Medicine, Mahidol University, Thailand)Professor Pedro Politi (Oncologist, University of Buenos Aires, Argentina)Professor William Powderly(Director, Institute of Clinical and Translational Research, Washington University in St. Louis, USA)Dr Christophe Pouzat (Mathematician, CNRS, France)DrDavid Price (Statistician, Doherty Institute & University of Melbourne, Australia)Professor Richard Price (Clinician,Menzies School of Health Research, Australia)Professor Sasithon Pukrittayakamee (Clinician, Mahidol University, Thailand)Dr Aung Pyae Phyo(Clinician/Scientist, Myanmar Oxford Clinical Research Unit, Myanmar)Dr Ben Saville (Statistician, Berry Consultants & Vanderbilt University)Professor Jason Roberts (Pharmacist/Clinician, The University of Queensland, Australia) Professor Frank Rockhold (Biostatistics/Bioinformatics, Duke University, USA)Professor Stephen Rogerson (Clinician, University of Melbourne, Australia)Professor Philip Rosenthal (Clinician, University of California, USA)Professor Kathy Rowan (Researcher, Director of the ICNARC ClinicalTrials Unit, UK)ProfessorIgnacio Rubio(Researcher, University Hospital Jena, Germany)Professor Fiona Russell(Paediatrician, The University of Melbourne, Australia)Dr Sam Saidi (Clinician, University of Sydney, Australia)Dr Makoto Saito (Clinician/Epidemiologist,University of Tokyo, Japan)Dr William Schilling (Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Anuraj Shankar(Clinician/Triallist, Eijkman-OxfordClinical Research Unit, Indonesia)Professor Sanjib Kumar Sharma (Clinician, Koirala Institute of Health Sciences, Nepal)Professor André Scherag (Statistician, Jena University Hospital, Germany)Professor Ilan Schwartz (Clinician/Researcher, University of Alberta, Canada)Professor Julie Simpson (Statistician, Universityof Melbourne, Australia)Dr Andre Siqueira (Medical researcher, Fundação Oswaldo Cruz, Brazil)Professor Frank Smithuis (Clinical researcher, Director of the Myanmar Oxford Tropical Research Unit, Myanmar)Dr Tim Spelman (Statistician, Karolinska Institute, Sweden) Dr Kasia Stepniewska (Statistician, University of Oxford, UK)Dr Nathalie Strub Wourgaft (Clinician, Drugs for Neglected Diseases initiative, Switzerland)Professor Darrell Tan (Clinician-Scientist, University of Toronto, Canada)Professor Christoph Thiemermann (Head of Centre for Translational Medicine & Therapeutics,Queen Mary University,UK)Dr Aimee Taylor (Statistician, Harvard T.H. Chan School of Public Health, USA)Dr Walter Taylor (Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)ProfessorAntoni Torres (Clinician, University of Barcelona, Spain)Professor Guy Thwaites (Clinician, Director of the Oxford University Clinical Research Unit, Vietnam)Professor Tran TinhHien (Clinician, Oxford Clinical Research Unit, Vietnam)ProfessorGeorge Tomlinson (Biostatistician, Mt Sinai Hospital, Canada)Professor Steven Tong (Clinician, University of Melbourne, Australia)Professor Paul Turner (Clinician/Researcher, Director ofCambodia Oxford Medical Research Unit, Cambodia)Professor Ross Upshur (Head of Division of Clinical Public Health, University of Toronto, Canada)Professor Rogier van Doorn (Clinical Microbiologist, University of Oxford, UK)Professor Lorenz von Seidlein(Clinician, Mahidol Oxford Tropical Medicine Research Unit, Thailand)Dr Dee Dee Wang (Clinician/Researcher, Henry Ford Health System, USA)Professor Sir Nicholas White (Clinician,Mahidol Oxford Tropical Medicine Research Unit, Thailand)Professor Thomas Williams (Clinician, KEMRI-Wellcome Trust Research Programme, Kenya)Dr Martin Sebastian Winkler(Clinician, University Medical Center Gottingen, Germany)Professor Chris Woods (Researcher, Duke University, USA)Dr Charlie Woodrow (Clinician, OxfordUniversity Hospitals NHS Trust, UK)Dr Sophie Yacoub (Clinician, Oxford University Clinical Research Unit, Vietnam)Professor Marcus Zervos (Researcher, Henry Ford Health System, USA)

For me, this is the biggest disgraceful scandal of the whole epidemic. It's absolutely clear that the paper in the Lancet was entirely fake.
Reminds me of Phase V.
On the basis of this, WHO halted other HCQ clinical trials, and some countries who were using it have stopped using it.

"A mysterious company’s coronavirus papers in top medical journals may be unraveling"
https://www.sciencemag.org/news/2020/06/mysterious-company-s-coronavirus-papers-top-medical-journals-may-be-unraveling

"Studies That Most Likely Led WHO to Halt Hydroxychloroquine COVID-19 Trials are Under Fire Amid Questionable Data from Surgisphere"
https://www.sciencetimes.com/articles/25918/20200603/studies-led-who-halt-hydroxychloroquine-covid-19-trial-under-fire-questionable-data-surgisphere.htm

"Concerns regardingthe statistical analysis and data integrity"
https://statmodeling.stat.columbia.edu/wp-content/uploads/2020/05/Open-Letter-the-statistical-analysis-and-data-integrity-of-Mehra-et-al_Final-1.pdf
(Signed by 150 physicians and scientists from around the world)

"Disputed Hydroxychloroquine Study Brings Scrutiny to Surgisphere"
https://www.the-scientist.com/news-opinion/disputed-hydroxychloroquine-study-brings-scrutiny-to-surgisphere-67595

"A Study Out of Thin Air"
https://www.medicineuncensored.com/a-study-out-of-thin-air


Any who reads these links will surely conclude the same as me.

Agreed, Lykiri.
Thanks for update snippet.

Hi meirluc.
I suspect Ex is broadly right on this from his look at the curves.

I tend to come at this from the other end. Which is that I don't think that alphapuppy's model predicting such an amazing p value in favor of DCVax treatment on PFS can be right, because I don't think the p value can be right.
If it was, then they would most probably have received a 'halt for efficacy' rec from the DMC back in 2015, and we would have AA by now.
So I just assume that the modelling has limited validity for one reason or another.
It's just a model, in the same way that all those Covid models were.
When the curve turns into a completely flat straight line, I just think 'I don't know what this really means and does it mean anything?'
A bit like the infamous Optune high compliance curve that turned into a flat line, and which didn't really mean anything.

I'll confess to not really liking KM curves, as I find them difficult to interpret fully. Though they can tell you important stuff sometimes. Crossing survival curves is the prime example for me. That is seen in many ICI trials where mortality on the treatment arm is higher than on the control arm, before things switch around with further time duration. You can see that at a glance.
Plus crossing curves also tells you you don't have proportional hazards.

In the case of Alphapuppy's video, I didn't even scrutinise the curves too closely, because I find them difficult to interpret, and I've already assumed they must have a large inaccuracy factor.

And on the IMUC trial, there were only 42 control patients.
To what extent can 42 patients from another trial in another time and another place actually inform you how DCVax control patients will PFS perform?
Not very much, I think.
And as with OS, measuring PFS by median in our trial is not a good idea (if you want to best elucidate the benefit). It doesn't capture all those long term survivors, who not only survive, but do so without progressing (just like Brad). So if NWBO are going to use PFS in the final analysis, they are likely to employ restricted mean progression-free time.
It means a lot to a patient if you don't just survive, but you do it without any recurrence of disease. You are not only living longer, you are also living better. Most of this group are undoubtedly meth.
We know that unmeth patients comparatively, didn't do very well in the trial, so I doubt there will be a huge difference in PFS between control and treatment for that group, frankly. Certainly not by a measure of the median.

Alphapuppy has acknowledged that his model is based on scant input data, and comes with big assumptions.
And it's not my intention to be critical for the sake of it.
It's very welcome.
But personally, I don't read too much into it, in terms of predicting the PFS delta in our trial.

Thanks Senti.
'Wreaks havoc'.
Yep that was it. How could I forget?!

We really don't know what is the status of PFS in the final SAP.
I'm inclined to think that the 'emphasis' is more on OS now, but we really don't know about how the alpha split might have changed.
It seems sensible to assume they ran the trial as long as they have done, because they believe they need the very mature OS data.
And we don't know what the regulator(s) attitude is about accepting an adjudicated PFS outcome anyway.
As I've said previously, the little hints, if there are any, suggest OS is the main focus.

But I might be wrong.
A lot depends on what the DMC did report to the company after the putative efficacy IA.
There is still the possibility that the DMC unblinded look found that the data was overwhelmingly good at that point, and that is why a regulator might have advised that all further recruitment was to go to treatment (or so it seems).
That's the glass full interpretation, and it has never been disproved.
But personally, I don't think that is what happened.

You can see from the video that although the IMUC treatment arm achieved an advantage over control, separation between the arms was not quite good enough for stat sig. Part of this was because their ITT was really not big enough, only 124 patients.
So they needed a wider separation to achieve stat sig than we will, because of our larger ITT.
Their delta was better on PFS, but OS was their primary I think.

I'm sure alphapuppy can tell you himself, but using the IMUC control arm gives you best chance of a like for like control arm / control arm comparison, which is what he applied to his model.

You can see the IMUC delta in the video from this point:-

Hi alphapuppy.
Thanks for the model.
Do you think that possible L related pseudo-progression won't be an issue in practice, when quantifying the PFS delta? Or just a small issue that won't affect the result?
We don't know that immunotherapy pseudo-progression is an issue that could cloud PFS results in this trial. But we do know that NWBO felt the need to convene an expert panel to adjudicate on PFS calls. And Dr Bosch made that remark back in 2015 I think, about pseudo-progression confounding trials. Can't remember the actual word he used. It wasn't 'confounded' but something similar. And he was referring to immunotherapy trials in general rather than the L trial in particular.
The mystery remains as to whether there was an efficacy analysis in Summer 2015, and what was its outcome. It was after that time that we had first reference to an adjudication panel. Which leads me to hypothesise that PFS wasn't quite good enough at that time for a trial halt with an AA application.
AV notably, took it to mean that the trial had failed. I never took that view, but did feel that perhaps PFS had fallen short of the company's best expectations.
Your model suggests that all of the control arm have progressed, whereas we know that approx 50 patients in the entire ITT hadn't progressed when LL presented in March 2019. We have long assumed that the vast majority of those 50 were on the treatment arm.
Perhaps indeed all of them were. That would be around 15% of the treatment arm remaining progression free as of March 2019.

Alphapuppy used the control arm data from the IMUC trial as the basis for his modelling. Not the treatment arm. As such, the performance of the IMUC treatment arm is not relevant to the model.

Lol. So you still think that all know this needs to return to 0.17?!!

Surely only those with a short position 'need' this to return to 0.17?

I knew there was a similarly named firm in the US. Not sure if this is that one. But this announcement is nothing to do with the Advent that is NWBO's manufacturer.

Then there is the Advent that comes before Xmas...
(I'll get my coat...)

Ah. I didn't know about the 'independent SAGE'.
I will follow with interest. I can also see an 'alternative' independent SAGE coming in to existence, because there is a wide spectrum of scientific opinion, some of it quite polarised.
On the possible emergence of a second wave, I remain of the view that it will be almost zero in some countries, rising to perhaps moderate in others, with the countries who have deepest lockdown the most vulnerable to another spike.

But if a second wave is about recorded cases but not deaths, then that is really no bad thing.
We don't have widespread serological testing yet, and the tests are still unreliable. But in basic terms, the more individuals who have already been exposed to Covid, the better.

Because the remaining pool of susceptible individuals will get smaller and smaller, leading to a diminishing R number, and the eventual end of the epidemic.

As you say, we will see.

SAGE, of course, is not independent.
If they were required to register their interests, which of course they should be, you would quickly see that.
Clearly this guy doesn't have accurate information if he can quote 8000 daily new cases. That is tantamount to sloppiness at best or scaremongering at worse, imo.
Whichever way you look at it, the UK Govt has made a complete arse of things. On that we can agree.
On the official figures; are they inaccurate? Yes.
But which way inaccurate? Over-inflated or understated. Nobody really knows.
I'm inclined to the view that it's not the Govt controlling the scientists, but rather the scientists controlling the Govt. And the SAGE scientists are very well known for their connections and affiliations, though they don't declare them...

If you are open to the whole range of views of scientists and doctors that are not controlled by the Govt, then here's a couple that are very different to those of Sir David King:-

I wasn't thinking about LTFU patients. With regards to that issue, I'm assuming that contact-tracing attempts were begun as soon as those patients went LTFU, and that attempts will have continued ever since. I doubt if any relatively recent Covid restrictions will have made any significant difference to the locating of the small pool of actual LTFU patients. If missing patients haven't been found in the last few years, then they are unlikely to be found now.

I think it's more a case of a few patient records that might have become 'unavailable for follow-up' due to Covid restrictions.
Clearly, this is where the local investigators are important, to try and find solutions to any situation whereby an individual patient file cannot be signed off, because of a small but necessary part of data confirmation still remaining unachieved.

(Though if they have added some element of 'patient-reported outcomes' to the SAP, such as a Q of L survey, then that would require direct patient contact...)

I'm not sure what you mean by; 'I wouldn't wait.' You still have to wait before you can do final datalock, upon which all your trial data and its subsequent analyses and its use in a regulatory submission will be based.
So what is it you wouldn't wait for?
What is it that you think that a soft lock actually enables you to do?
It's not a concept I'm familiar with, so its practical purpose isn't immediately obvious to me.
I can only see that it might allow for a provisional stat analysis, with perhaps broad provisional findings, a bit earlier than otherwise. But it doesn't accelerate hard datalock.
But as I said previously, the fact that they are even talking about adding an interim stage (soft lock), means to me that hard datalock is likely a few weeks away, rather than a few days away. Otherwise there would be no reason to even consider a soft datalock.
But as long as the company (and its CRO) are doing all that can be done to achieve final datalock, then that is all we can ask.

The only other thing I would add, is that we don't know what, if anything, is happening with the Panel adjudication of PFS calls.
Is it completed? I have no idea. Are Covid restrictions delaying its completion? I don't know. Is a completed PFS panel adjudication an essential element requiring completion before unblind? I don't know...
All depends on the final version of the SAP that they settled for.

Indeed is the SAP itself possibly subject to some late amendment due to Covid-related issues?
Probably best not to go there....

So what is the benefit of a soft lock?
None, as far as I can see.
Unless it allows statisticians to get an advance look. But what benefit does that offer?
I suppose if the stat guys can do a provisional analysis before hard lock, they should need less time after hardlock. That's about all I can see.
Might save a week or two, I suppose.

If they firmly anticipated getting to datalock in 2 weeks rather 4, I'm sure they wouldn't have made mention of 'soft lock'.
It's precisely this reference to soft lock, that makes me think we are probably looking at a month or more to full datalock.
Which if it has to be, it has to be.
As long us the delay is due to a factor that they couldn't have been expected to account for, and is out of their hands.

They just need to keep us posted with all possible detail.
The enemy is nil info or scant info, in the next few weeks.

Just my opinion.

Not sure where your figures are coming from, abc.
In fact I'd like to know. Who issued those figures?
According to Worldometer, which gets its figures from the UK Govt., the UK only went above 8000 new cases in a single day once, and that was on April 10. About 7 weeks ago. That was the peak of new cases.
For the last week, new cases have been below 2000 each day, a quarter of what you suggest. This is despite there being a much higher rate of testing in the last few weeks. This case rate is bad enough and much the worst in Europe. Particularly when one recognises that the UK has more deaths per positive test reported than just about anywhere.
If you look at the corresponding decline in cases and deaths in just about every country in Europe, you will see that things are clearly not getting 'decidely worse'.
This information is readily available and may ease your fears.

It's been estimated that 50,000 will die of Cancer if cancer treatment is not resumed until September.
In most of the country 'shielded' individuals are more likely to die because they are being shielded! A fit and previously active 80 yr old, who stays indoors for several months will see health deteriorate quite quickly.

https://www.worldometers.info/coronavirus/country/uk/


All the countries in Western Europe have the same pattern, with new cases peaking at the end of March or the first or second week of April.
I think the more important question is why the UK has the worst figures in Europe! And I could advance many reasons for that.
Certainly in Germany, the mortality figures are a fraction of what you would see in a flu season.

There is of course no rationality to the policy on quarantine for incoming visitors and in particular its timing. The UK has continued some air traffic throughout the crisis somewhat mysteriously.

Good for whom or what?
Do you mean that it is basically inert?
(No problem with that, if that is what you mean..)

Well, the market is clearly perfectly fine with being updated.
It's what they said they would do. It's what I advocated for, and they've done it.
For sure, we would have preferred datalock, but, as I suspected, unavoidable delays (seemingly), have come into play.

I have no idea exactly what a soft lock is, and I can't see what benefit at all it could offer, though I could see some harm. I think they shoud ditch this notion.

The way I read this, we may or may not be looking at more than a month of delay.

So yes, another update in two weeks please.

Yes, but it's a bit obscure.

So the UK has been left out of lots of multilateral agreements to open borders. The UK has a higher per capita death than Sweden and any other UK country bar Belgium.
I don't hear you raise criticism of the UK (or France or Belgium).
You seem to reserve your criticism for Sweden.

One of the things that people forget is that other things have been lost. The human right to physical contact. The hug, the handshake, the arm on the shoulder, everyday natural intimacy which is an important part of life. We have this situation in the UK, where vulnerable adults are 'shielded' at home often alone. Basically instructed to 'be' isolated in something that amounts to house arrest.

In the archetypal microcosmic situation that is the supermarket, we now have people late in the day adopting mask-wearing (about 2 months after when it really would have had a benefit) 2m measuring tape plastered all over the floor, nobody smiling, nobody exchanging casual conversation, suspicious glances being exchanged and one-way systems.. Woe betide you if you forget something two aisles back!

School staff in primary schools are measuring out spaces between desks in preparation for eventual re-opening. For young children starting out this has become 'normal'.
Tragic.
And because of the new app which is about to start woe betide you if you come within bluetooth range (maybe on the bus or the tube) of someone who logs symptoms. Straight into 14 days self-isolation you must go. Do not pass go. Do not collect £200.
You will almost certainly be perfectly well. You still won't be offered a test that could all clear you. You might live alone. You might already be socially isolated. Maybe you can't get or can't afford home grocery delivery.
And all this when deaths and infections (even in the UK) are rapidly on the wane.

Now Sweden will not have this intensity of negative social experience. And that is worth lots..

Well, of course there is space for lots of disagreement on the many, many factors that played an influence on the death rate in any particular state or country. But some things are not in dispute.
Such as the economic decimation, (and all the long term health consequences of that), and how national responses played into that.

I don't disagree with your remarks about NY at all.
But in the same way as urgent responses in that location to the first wave were clearly too little, too late, I think the same could apply to national easement not of only of physical restrictions, but also there needs to be an attempt to diminish fear in citizens, rather than keep ramping it up.

Why compare Sweden to Norway?
Goegraphical proximity has limited relevance.
You could equally say why does Belgium have eight times the mortality of Germany, when they share a border.

The US itself will indeed be a fascinating case study, when state by state analysis eventually happens.

Purely from the view of the biggest killers in western societies, namely cancer and heart disease, a speedy resumption of proper treatment in these areas is imperative.

And that includes bringing safe and effective treatments such as DCVax into availability.

Yes, most definitely. But virtually all the extended lockdowns were predicated on a singular lack of evidence.

The indisputable evidence of declining deaths is there for everyone to see.
(Clearly countries and regions of the world that experienced the outbreak later, such as Brazil, Mexico, Russia are not so far along the curve.)

But once again, I'll state this trend is clearly good news for the world at large.

A worldwide ban by the UN on animal 'gain of function' studies will perhaps reduce the risk of recurrence.

That didn't hold true for the last two coronaviruses SARS and MERS.
So I doubt it will hold true for Covid.
Time will tell.

In terms of broad rates of fatality in different countries, it is beginning to look like it doesn't matter how you got there, the outcome is not going to be wildly different, regardless.
As lots of eminent scientists have been saying for some time now.

Though the countries that instituted the strictest lockdowns in an attempt to put the genie back in the bottle will be more liable to some sort of resurgence of cases, though even that will likely be moderate, with much reduced fatality.

I imagine there will be commissions of enquiry instituted in many countries in the next couple of years to look at the mishandling by Govt's and public health agencies, so that lessons can be learned.

Certainly, the excess mortality caused by the closure of societies, both in the here and now and in the years to come, will be a huge multiple of direct Covid deaths.

But however way you look at it, it's good news that the epidemic is clearly coming to an end.

Yes, of course it's a feed.

But they have picked it up and reported it.