An ongoing dialogue on HIV/AIDS, infectious diseases,
August 24th, 2020
FDA’s Emergency Use Authorization for Convalescent Plasma for COVID-19 Seems To Be Fooling No One
Starting late Saturday night, and proceeding the next day — like a relentless series of coming attractions for a blockbuster summer movie or the finale of a reality TV series — we repeatedly heard word that the President planned to make an announcement Sunday evening about a “major therapeutic breakthrough” in treatment of COVID-19.
6 p.m. Eastern. Live. Get ready. Here it comes.
And, satisfying the ratings-hungry entertainer he once was (and some would say still is, though “entertainer” must be used cautiously in this context), we turned up to hear him cite this “powerful therapy” that “had an incredible rate of success.”
No, it’s not hydroxychloroquine.
This time it’s convalescent plasma. That liquid gold harvested from recovered COVID-19 patients, swimming in antibodies directed against SARS-CoV-2, and also containing a veritable secret sauce of illness-reversing substances that have fascinated doctors and scientists for decades.
Never mind that harvested convalescent plasma isn’t used commonly to treat any infection currently.
Or that the randomized trials of this treatment have so far been disappointing.
Or that the observational data the FDA used to justify their action come from an unpublished study not yet subject to peer review.
(Here’s the next best thing, for those inclined to take a deep dive into data analysis.)
Or that the very experts employed by the government to review plasma’s safety and efficacy have as recently as last week raised important concerns about the lack of convincing evidence for this treatment.
Or that this action by the FDA will almost certainly jeopardize any existing randomized trials of convalescent plasma in the United States.
Or that the person from the FDA who reviewed the plasma data had his name redacted from the memo.
Or that the emergency use authorization may make patient care more difficult, since this will necessarily be a limited resource — especially if antibody titer turns out to be a critical determinant of whether this works, and since antibodies appear to fade in many people soon after they have COVID-19.
Nope — no matter. On the evening of a major political event — timing that cannot be coincidental — the president got his ratings.
He had to do a little intimidation, but we’re getting used to that.
The deep state, or whoever, over at the FDA is making it very difficult for drug companies to get people in order to test the vaccines and therapeutics. Obviously, they are hoping to delay the answer until after November 3rd. Must focus on speed, and saving lives! @SteveFDA
— Donald J. Trump (@realDonaldTrump) August 22, 2020
The good thing is that no one in the scientific community is fooled. I have not heard from a single ID specialist who believes this action was supported by existing data, and indeed our professional society agrees.
Convalescent plasma may work to help people with COVID-19.
But if it does, we don’t know how much, or who are the most likely to benefit, or how to select the right donors.
Because given the absence of controlled trials, right now in the U.S. what we have are 70,000 anecdotes — that’s how many people have received it in this country — tied together by individual reports and separate observational studies.
For the true evidence, we’ll have to wait for the randomized, controlled clinical trials.
The ones going on in other countries.
41 Responses to “FDA’s Emergency Use Authorization for Convalescent Plasma for COVID-19 Seems To Be Fooling No One”
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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I read very brave personal comments against Trump disregard of science on twitter or in the newspapers. What is lacking is an organized response or demostrations from scientist in support of good science and against intimidation of the FDA and CDC to change their professional recommendations.
Let’s organize demonstrations. The scientific community has been bullied for too long and it’s ridiculous to trick people into trusting social media memes and conspiracies instead of reputable scientists. Let’s do it.
Why aren’t ID doctors rioting?
I can’t recall what the date of the March for Science event was a couple of years ago, but if the anniversary of that event might be approaching it may be time to have another one with this theme.
A new insane statement coming from a Country president, which is somewhat understandable as a political marketinian strategy.
But the FDA?. What about the once a first-rate science agency in drug regulation?
Following their overestimation in efficacy of remdesivir, now it comes this second bullet.
Hope the european EMA agency will be more strict in its evaluation.
I agree with one of the other responders to this blog post that there needs to be an organized response from the scientific community about the lack of good science supporting this EUA approval, the intimidation and political showboating of the FDA and the lack of commitment of the FDA to the well-being of the American people by giving in to the intimidation and showboating. With this action, there is now virtually no chance of completing any of the scientifically rigorous, high quality randomized clinical trials that are underway to actually evaluate whether convalescent plasma has any role in the treatment of Covid-19. Also of note, every other clinical trial of new/novel antiviral and adjunctive therapies for Covid-19 exclude persons who have received convalescent plasma, so this action also takes a large pool of potential participants in other clinical trials out of that pool, making it harder to enroll other scientifically rigorous randomized clinical trials. This is a travesty of enormous proportions!
So far what i see hear are accusations of intimidation without the slightest shred of evidence. If you were dying of a disease with no cure other than “supportive care,” would you want the right to try it? No one has forced ANY DOCTOR to prescribe it. Try and keep your vitriol to yourselves.
First of all, there is a difference between dying of a relatively rare disease for which there is no cure other than supportive care, and dying of a pandemic infection, which is affecting millions of people.
If I had life-threatening Covid 19, I would not want to “try anything” that was on the pharmacy shelf without evidence of safety or efficacy. What I would do, however, is consent to join a clinical trial to actually evaluate safety and efficacy of a potential treatment.
By opening up convalescent plasma to all-comers, there is little likelihood that we will ever know whether or not it is effective, and if so, at what dose, and at what point of the illness. I hope that the European regulatory agency is less susceptible to intimidation by an ill-informed and opportunistic ‘leader’.
Read the NEJM. Dexamethasone: https://www.nejm.org/doi/full/10.1056/NEJMoa2021436.
Remdesivir: https://www.nejm.org/doi/full/10.1056/NEJMoa2007764.
In contrast, there is no convincing evidence that hyperimmune serum shortens the duration of illness or improves survival rates.
Promoting unproven treatments wastes resources and damages the credibility of scientists. They are our best and only hope of stopping deaths and preventing more cases.
Clearly, your wish to support the President is greater than your desire for scientific/medical clarity in decision making.
The tweet shown is enough to show intimidation – if that is not enough ‘evidence’, then, nothing else will suffice.
The more concerning issue is more fundamental – so much wrong data/recommendations are coming from the WH that this is making people confused, and loose trust in institutions. Even an august body like the FDA has its reputation sullied here.
The fact that no one is forcing any doctor to do anything is not even relevant here.
Medicine as a whole runs on trust – if you muddy the waters for political purposes, people will loose trust.
What seems more shocking than lies and irresponsible decisions from the President is Commissioner Hahn’s statements grossly overstating the favorable impact of plasma. Aside from the inconclusive nature of the data, the numbers he gave were very misleading. He walked those back today, after the horse was far out of the barn.
This does not bode well for a potential October surprise. The Trump administration has indicated that they want a vaccine approved before the election, but it seems extremely unlikely that there will be sufficient evidence to do so. Approval of an unproven vaccine would be enormously damaging to efforts to use any vaccine eventually proved to be effective, and would probably have an adverse effect on other vaccination efforts, as well.
It is reported that Russia has already geared up production of their SARS-CoV-2 vaccine without bothering to conduct phase 3 trials. I’m sure we could get plenty of that from Vlad if an EUA for it was approved.
It is not that shocking the FDA commissioner Hahn succumbed to badgering from the president. At least Francis Collins and Robert R. Redfield, who are equally spineless, denounced convalescent plasma as proven therapy for COVID-19. The big concern is vacillations and inconsistencies, perceived by the public, in the positions of the CDC and the FDA will seriously erode confidence in whatever SARS-CoV-2/COVID-19 vaccine that gets licensed eventually. A bigger concern is that the anti-vax noise is going to get much louder. The repercussion on immunizations generally may be unfathomable, speaking as a pediatrician. Unfortunately, the only credible/sane voice from the government, Dr. Fauci, has been silenced fro now by his laryngeal polyp. What a bad timing on the part of the polyp! Time to queue up for the Russian COVID-19 vaccine!
I look forward to your post promoting Convalescent Plasma on the first Wednesday in November.
This action is a way of moving the government and regulation out from between the patient and physician. They can discuss the treatments available and potential risks and benefits. The patient can then make an informed decision based on their symptoms and risk tolerance. This is exactly what you do in a crisis. You act, you move, you try, you accept increased risk. What you don’t do is wait for nose picking scientists working 8A-5P to publish their randomly controlled double blinded study in 2023. Regardless of your political leanings this is a move that a leader makes in a time of crisis.
Um.
You do know that there have been over 24 million cases of Covid-19 since the outbreak began less than 9 months ago? And that over 850,000 people have dies of it? And that the USA leads the world in the incompetent management of this crisis?
Nose picking scientists won’t have to wait until 2023 to publish a RCT unless leaders with little or no scientific expertise and even less grasp of the situation interfere, make ‘decisions’ and boldly blunder on seemingly ignorant of the role they are playing in making a bad situation much worse.
I would rather have a scientist with an understanding of infectious disease make the difficult decisions than the ignorant buffoon who is pretending to be a leader in a time of crisis.
Just saying…
Not sure if you’ve handled crises, but I have. This includes a volcanic eruption with 110,000 evacuees, earthquakes, typhoons, and nationwide epidemics. The most important thing to do is step up and use science-based tactics. You need to inform and persuade political leaders to use these. Otherwise, they tend to waste resources battling phantom threats or panicking and placing restrictions that prevent emergency workers from doing their jobs.
The last thing you do in a crisis is to ask victims and individuals to decide what to do. In a crisis, good leaders consult experts and make science-based interventions.
In a crisis, good leadership involves making good decisions and then persuading or forcing people to follow. Think Eisenhower at Normandy, the SARS epidemic, and the eradication of smallpox.
Well said. Thank you..
The reports from American Journal of Pathology, lead author Eric Salazar,in pre-proof form describe the experience from Houston Methodist Hospitals with 316 Covid 19 patients treated with convalescent plasma compared to a propensity matched group. The data appears compelling and suggests that plasma from recovered patients with a high titer to RBD , when given within 72 hours resulted in a significant reduction in mortality (P=.047). The larger Mayo trial, published in medRxiv reaches similar conclusions.
Clearly the efficacy issue requires a double blind RCT.
Until then, the question is whether or not to employ this modality of therapy in individuals who are terribly ill. We are seeing a storm of publications coming out fast in order to advance discovery and improve care. Perhaps reviewers later will find serious errors requiring the authors to withdraw their manuscripts. We saw this already with the Lancet article authored by Mehta. What an embarrasment that was!
From the perspective of the FDA, the key question is what action it should take to improve the outlook of these very ill patients. At both hospital centers in the area where I work, convalescent plasma is being routinely offered. Sometimes, physicians on the front lines, have to make a best judgement call and this seems to be such a situation. Also, there is an argument that the proper role of the treating physician is to present the best data available, give an informed opinion and then let the patient or his family make the ultimate judgement on acceptance of a specific treatment. After all, the final decision rests with the owner of the body in question. There might be individuals who would choose plasma therapy when presented with the available data, whatever any one of us might think. And there might be others who would decline.
Who has the right to choose for the patient?
It is clear that some of the writers in this space have powerful opinions regarding the vertebral strength of the FDA commisioner, Francis Collins and Robert Redfield. The last two individuals have proven to be thoughtful scientists in the past. It seems a bit much to show such disdain to them. May I suggest limiting the discussion to the actual facts and analysis.
All are desperate for hope. In rushing to promote unproven treatments, Trump, those he intimidates, and those who pull the strings of both, prolong rather than shorten the duration of the pandemic. True leadership will come from those willing to tell the truth. Thanks for doing so, Dr. Sax.
With the demonstration that high antibody titer plasma given early was beneficial in reducing mortality, and that the therapy is incredibly safe, in a crisis situation such as this one, it is perfectly appropriate to deploy this therapy. Even if a fraction of individuals, say 25% are able to get timely plasma with a high titer and have an absolute reduction in mortality of even 25%, that’s something. Especially since the therapy is deemed very safe. Trump may have used the ocassion to his usual theatrics and inappropriate behavior but that doesn’t concern me. I am letting my beliefs about him alter my clinical sense that some benefit may accrue from plasma therapy. RCT obviously take time, and the paperwork involved in the EAP was incredibly burdensome. That had to be relieved. We weren’t getting paid for that work of entering so much data for each patient and got no credit for any coming publication. But generally “experts” men and women of science don’t work in the field but for a paltry month or two of the academic year. Residents, fellows and clinical faculty do the bulk of work. Pardon me, I don’t trust anyone who is deemed an expert and has less clinical experience in direct patient care than in combing through literature, writing grants and self promoting papers, which, incidentally, in 80% circumstances are observational and not replicable. Talk to John Ionaddis at Stanford. The bulk of published literature is poor quality. At least this observational series was 35000 patients large. Safety data based on 20,000 patients. Goes to say, deemed “expertise” does not confer wisdom.
Ultimately, if infusions of plasma with high titers of anti-COVID-19 seems beneficial, the better and more long-lasting solution is COVID-19 hyperimmune globulin which would require safety and efficacy data and FDA approval. Also, the timing of the therapy is probably very important and could be evaluated in studies of early vs later treatment. Meanwhile, history has apply shown that the politicization of science is very harmful. Several hyperimmune globulins have been shown to be effective in viral infections, mostly in prevention and early amelioration.
“Given early” begs definition especially when the death rate is One percent. There is not enough convalescent serum to give to every positive swab positive case. Awaiting the appearance of severity by definition is not early. That said ant combination of rational therapies before or after the appearance of progressive illness is justifiable.
With the Presidents current M. O., “hurry up, try something”, we don’t need to just throw in compassionate use of existing drugs. After all, why shouldn’t anti- malarials, antibiotics and the newest breakthrough, de-worming medication work? Aren’t viruses just another infection. We also should jump on Mr. Pillows Oleander breakthru. He wants to get that poisonous product an Emergency use designation ASAP. No matter that it hasn’t even had phase 1 or any human trials.
Personally, I’ve always thought Ice Cream Cones should get emergency use designation. Even if they don’t work, the Patients would benefit from a brief period of joy and hope.
I have heard from many people that their Covid got dramatically better once they had just one Ice Cream Cone! It’s very clear that this works, even for prophylaxis. What is wrong with the Deep State FDA? What are they waiting for? Proof??? Sad.
The point is not whether convalescent plasma is effective and safe. That is not known yet. And the point is not whether to withhold convalescent plasma from sick patients. The point is to capture useful data every time convalescent plasma is used. To do that, we must enroll every recipient of convalescent plasma into a randomized trial in order to objectively assess effectiveness and safety.
Many other therapies are being considered as well. Should FDA also fast track approval for Oleandrin, derived from a plant with known toxins, just because “the pillow guy” says, without objective data, that it cures Covid-19?
Agreed. Clear evidence of clinically significant changes in outcome is needed first.
Based on the available observational studies, the best case scenario is an NNT of 21 when administered to severely ill hospitalized patients (52% ICU admission), within 3 days of disease onset.
As a human blood product, convalescent plasma has a limited supply, known risks, and high variability. Comparison to other hyperimmune globulin treatments is premature as we don’t yet know if hyperimmune donors will have persistent high IgG levels, nor if all hyperimmune donors have sterilizing immunity.
It is responsible science and medicine to acknowledge the uncertainties, and effective policy to educate the public about the scientific process in confronting an evolving state of knowledge and therapeutics.
Easy to throw political stones, but medicine has done little better.
Don’t wear a mask. Then do wear a mask. Keep 6 feet distance. No 6 feet might not be enough. This large group setting is bad, while that one gets a pass.
All information comes out as “May, might , possibly, could be, potentially, we’ll see”. And then there is wonderment at why the public doesn’t seem to listen or heed advice.
That’s false equivalence. There’s a huge difference between “we’re not sure how effective masks are based on current evidence” and hyping up hydroxycholoroquine or convalescent plasma as if they were proven therapeutic breakthroughs when there’s no solid evidence to back that up.
For prophylaxis in aged care homes as soon as a patient(s) are detected or suspected positive it ought be trialled .
The mortality rate there is 15-25% and aged care workers are at risk so a trial and urgently is just .
Pre Travel HyperImmune Hepatitis B immunoglobulin was used a lot to protect against Hepatitis B before the vaccine and also after inadvertent needle stick injury .
Recently it has been used for measles outbreaks .Precision Monoclonal antibodies are in rapid development and review .
I am a veterinarian that treats horses. In 35 years of practice I gained a lot of respect for “Convalescent Plasma.” Most was used for prevention of R. equi in foals…but also for other diseases. In Foals there is supportive research.
But also, observation over time…even though anecdotal is important. MOST important advances in medicine have been made by a keen observer. The small pox vaccine, penicillin and in recent years Helicobacter/ulcers.
Rich Estes
I have never seen such enmity by the medical community directed against a sitting president as there seems to be against the current one and that includes Dr. Paul Saks obviously.
The truth is that many Americans have died unnecessarily from this pandemic right from the beginning due to the arrogance and political leanings of physicians at all levels.
That includes giving the wrong public health advice for the general community by the top experts, providing the wrong care in the hospital and withholding of potentially effective treatment in both cases.
I believe that when dealing with a deadly disease the ethical and moral obligation when it comes to the use of older tried and true modes of treatment is to offer those options under the proper conditions and after full disclosure rather than sit and wait for the completion of prolonged large scale randomized double blinded study conclusions.
That’s because there’s never been a president who shows such enmity toward science and scientists. There have absolutely been missteps by the public health community and by plenty of individual physicians along the way. That’s to be expected. We’re learning as we go. But that’s no excuse for politicizing science or the public health. This administration is erasing many decades of progress that FDA and CDC achieved under governments of both parties.
My understanding is that the emergency authorization just gives patients and doctors one more option. This article seems to miss the point.
“What’s beautiful about America is that we have the freedom to not wear a mask”
a citizen
Those of a certain political stripe can only care about the one individual in front of them at the moment. Those of another political stripe can care about everyone now and later.
The following paragraph is taken from the FDA mission statement on the FDA website.
“The Food and Drug Administration is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation’s food supply, cosmetics, and products that emit radiation.”
Given this public health role of the FDA, it seems to me that the key question for the FDA is not whether or not to allow convalescent plasma infusions, but to assure we have adequate information and the scientific integrity (without political influence) to come to a sound conclusion about the safety and efficacy of this and other treatments.
The real embarrassment is that we have a national “trial” that has infused 70,000 patients, but we are not even close to an answer. If this trial had been an RCT, we would have answers by now. We would be better off if the FDA was funded and empowered in situations such as this to mandate that clinical trials be randomized.
I can appreciate the anxiety an honest scientist feels about unproven treatments especially one that makes a political opponent score votes but at the age of 82 if God forbid I get infected l damn sure will try it!
Has anyone done the financial analysis? What is the cost per treatment? Will 3rd party payers (including Medicare and Medicaid) cover it. Is it like treating Kawasaki’s syndrome with High Dose IVIG? Please do the financial analysis resulting in treatment of 1000 patients to save 3.5 lives and share the results with Mr. Trump and Navarro.
I am interested to read more about the selection criteria and screening methodologies employed in the collection of post-infection Covid-19 plasma.
There are many examples of post deployment consequences from pooled blood products. can someone expand on this concern?
el plasma convaleciente aun no tiene autorizacion para uso clinico, solo para estudios de investigacion clinica, lo mismo sucede para el uso de otros tratamientos como hidroxicloroquina o remdesivir por citar estos dos, ya que todo esto ha ocasionado el uso mas comercial que clinico, ademas que dado que la pandemia ha ocasionado danos a la salud y economia han politizado y ocasionado usos de emergencia de tratamientos no eficaces, hay que esperar a tener un mejor conocimiento de esta enfermedd infecciosa emergente y el tratamiento o vacuna ,
It seems pretty clear from these comments that even readers of a august publication like the NEJM have succumbed to the Scylla and Charybdis of the therapeutic controversies surrounding COVID19. You have the majority (based on my perusal of responses) whose political bias is on full display as they interpret (often selectively and under the cover of being objective scientists) the ever-evolving data and information out there and do not hesitate to editorialize on the motivations of the President (a laymen) as he listens and absorbs the changing scientific landscape of the pandemic. On the other side, you have individuals who feel that the WH, the President, and others in government (CDC/FDA) are motivated not by the desire to make headlines and win votes but by a sincere desire to find answers that will help real people and real doctors. Science has always had a political side to it–ask any historian of medicine–but what we have seen in the last 8 months is the amplification of this such that it is now too often overtly politically self-serving and minimally is offered at warp speed and so invariably is often wrong or misleading.
What a shame. The truth as always lies somewhere in the middle and it might be best for those who have a platform and the aura of authority to be more circumspect in how they interpret and promulgate the emerging and evolving “science” of COVID19. Let’s be honest and admit we are feeling our way along here b/c of the perceived seriousness of the illness (at least in some patients) and since that may be the best we can do for some time our patients and our nation would be better served with more equanimity and charity and less effort to score political points. Trust is earned, whether you are a scientist or a politician or a friend. Fractiousness doesn’t promote trust, it erodes it.
What degree of trust do you presume the particular “politician” in question has in point of fact earned?