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Convalescent Plasma: The Unanswered Questions
“The data don’t show anything useful”
Problems with the government’s rationale for authorizing use of convalescent plasma in COVID-19 patients go far beyond the dustup over the purported 35% survival benefit cited by top officials on Sunday, numerous researchers say.
That figure quickly came under fire, leading to an apology from Commissioner Stephen Hahn, MD — but that’s not the only criticism leveled at the FDA’s analysis of the available data.
Much of it came from the Mayo Clinic and FDA expanded access program (EAP), at this point published only as a preprint manuscript. Although a large number of patients were included, the study was observational only, with no untreated control group. That makes the findings merely hypothesis-generating, and can’t offer any firm conclusions.
That’s fine for issuing an emergency use authorization (EUA), but not so much for making claims about survival benefit, independent researchers said.
“It’s not even a question of overstating,” Adam Gaffney, MD, MPH, a critical care doctor and health policy researcher at Harvard Medical School, told MedPage Today. “You can’t state much at all when you don’t have a randomized controlled trial.”
“People have made a big deal of Hahn referring to relative versus absolute risk reduction, but I think that’s less of a big deal,” Gaffney said. “The biggest problem is that the data they are citing … is not randomized. That’s the source of all the problems.”
Hahn took heat for saying that a “35% improvement in survival is a pretty substantial clinical benefit” further explaining that of “100 people who are sick with COVID-19, 35 would have been saved because of the administration of plasma.”
Critics rapidly took to Twitter, stating that the interpretation was incorrect. Hahn was referring to relative risk reduction, not absolute risk reduction. Thus, calculating the number of lives saved — which isn’t something experts recommend doing based on observational data in the first place — would have translated to somewhere more in the ballpark of 5 out of 100.
Moreover, the “risk reduction” came from a comparison of patients treated with high-titer plasma versus those receiving lower-titer preparations. The study offered no basis for concluding how many patients may have been “saved” relative to standard care.
And the 35% reduction in that analysis was for 7-day mortality; the relative reduction at 30 days was only 23%.
Hahn’s recital of the 35% figure “was just PART of the error,” tweeted Vinay Prasad, MD, MPH, of the University of California San Francisco. “The entire comparison is flawed. It is not a suitable control. The data don’t show anything useful.”
“The much broader problem here is the lack of commitment to performing large, national randomized controlled trials,” Gaffney said. “We could have done it for convalescent plasma. Instead, we did the EAP. I understand why people wanted it, but now we don’t know [if convalescent plasma works]. We have a question mark instead of a period.”
Undermining Trust in FDA?
Critics have charged that serious mistakes like Hahn’s misstatement could undermine FDA’s credibility, especially as it faces challenging decisions about potentially approving a vaccine this fall.
“This is playing out in the context of a hyper-politicized moment,” Gaffney said. “It behooves everyone to be extremely cautious in speaking about these things to avoid the appearance of politicization.”
On CBS This Morning on Tuesday, Hahn addressed concerns about politicization by offering reassurance to the “American people that this decision was made based upon sound science and data.”
In response to questions about the timing of the EUA announcement — it came just a day after President Donald Trump tweeted allegations that the “deep state” was holding back access to COVID-19 treatments with Hahn’s Twitter handle cited, and a day before the Republican National Convention got underway — Hahn said the agency had been working on the application for 3 or 4 weeks and was waiting on additional validation data, which were received at the end of last week and over the weekend.
“We’re going to continue to get data and as we’ve done with any other authorization, we will update that decision as new data come,” Hahn said on the news program. His agency initially issued an EUA for hydroxychloroquine, for instance, but later revoked it when the negative randomized trial data became available.
Lack of Access to FDA’s Data Review
Whether the public will ever see the full convalescent plasma data underlying the EUA is another matter. The “Clinical Memorandum” issued as the evidence behind the FDA’s decision glossed over the statistical analysis conducted by the agency; in particular, it made no mention of the 35% relative reduction in deaths.
Another problem with that is the 35% figure’s source isn’t fully clear. Although the EAP preprint manuscript is the most obvious source, Gaffney noted that HHS Secretary Alex Azar said it referred to a subgroup of patients under age 80 who were not on a ventilator. That is not found in the publicly available data. He also pointed to a tweet by FDA spokesperson Emily Miller that contains an agency slide showing a 37% reduction in mortality for non-intubated patients age 80 or under treated within 72 hours who got high-titer convalescent plasma, compared with low-titer product. Neither of those figures is reflected in the EAP manuscript.
The FDA did not return a request by MedPage Today for the full summary of data reviewed by FDA and any independent statistical analysis done by the agency.
Shmuel Shoham, MD, of Johns Hopkins University in Baltimore, said during a press briefing organized by the Infectious Diseases Society of America that “enormous amounts of data have been generated” from the EAP, in which more than 70,000 patients have been treated.
“Some data have been reported in articles and at meetings, but that’s only part of what the FDA — this is their program — has access to,” he said. “The stuff in the public domain is only a fraction of the data they have collected.”
Shoham is on the scientific advisory board of the EAP and is involved in two convalescent plasma clinical trials at Johns Hopkins.
Gaffney said Mayo researchers and FDA reviewers have noted that physicians were blinded to the dose of antibody given in plasma infusions, which he described as a “pseudo-randomization effect. We could use that to make more causal inferences about the effectiveness of antibody titers.”
However, he said there were some significant differences between those who received high-titer versus low-titer antibody, including differences in P-to-F ratio (a measure of inhaled oxygen to blood oxygen) and in those with five or more severe risk factors, suggesting the low-titer group was sicker to begin with than the high-titer group.
Also, patients in the EAP received a variety of other treatments: about half got steroids and 40% were given remdesivir.
“This is why we do randomized controlled trials,” Gaffney said. “Without them it’s very difficult to ensure that the effect you see is the result of the drug, and not the result of patient characteristics.”
Is an Answer Forthcoming?
Several randomized controlled trials of convalescent plasma are underway in the U.S., but the big concern is that wider access to convalescent plasma will limit enrollment. Will clinicians recommend that their patients enroll in a trial in which they might receive placebo? Will patients agree?
For the Hopkins studies, the prevention trial has enrolled 25 people out of a goal of 500, and its outpatient trial has enrolled 50 people of its 600-patient goal.
Liise-anne Pirofski, MD, of Montefiore Medical Center in New York, started a study at the end of April, looking to enroll 300 people. She said the team enrolled the first 150 people quickly, but “then the pandemic began to wane in New York.” With subsequent funding from the NIH, the trial has managed to enroll 190 patients, and has now expanded to four additional sites: New York University, Yale, the University of Miami, and the University of Texas Houston.
Clifton Callaway, MD, PhD, of the University of Pittsburgh Medical Center and lead investigator on the C3PO trial looking at outpatient convalescent plasma, said he hopes the EUA doesn’t discourage participation.
“To the contrary, I believe it should reassure persons considering participation that the FDA feels that convalescent plasma is safe and potentially useful and that the FDA specifically comments: ‘Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early in the course of disease.’ Giving high-titer convalescent plasma earlier (before you are sick enough to be in the hospital) is exactly what C3PO is testing.”
In addition to determining whether earlier or prophylactic treatment works, Shoham said other unanswered questions include identifying whether other components in plasma are useful therapies and whether low-titer plasma can work at all.
“What everyone agrees on is that the gaps in knowledge that exist can best be addressed by high-quality randomized controlled trials,” he said.
Pirofski said the science and data should be the focus, “rather than the decision and what drove the decision…. I don’t think anyone knows what drove that decision other than the people in that room. Hopefully they know.”
Top U.S. Officials Told C.D.C. to Soften Coronavirus Testing Guidelines
The Centers for Disease Control and Prevention abruptly changed its recommendations, saying people without Covid-19 symptoms should not get tested.
Trump administration officials on Wednesday defended a new recommendation that people without Covid-19 symptoms abstain from testing, even as scientists warned that the policy could hobble an already weak federal response as schools reopen and a potential autumn wave looms.
The day after the Centers for Disease Control and Prevention issued the revised guidance, there were conflicting reports on who was responsible. Two federal health officials said the shift came as a directive to the Atlanta-based C.D.C. from higher-ups in Washington at the White House and the Department of Health and Human Services.
Adm. Brett P. Giroir, the administration’s coronavirus testing czar, called it a “C.D.C. action,” written with input from the agency’s director, Dr. Robert R. Redfield. But he acknowledged that the revision came after a vigorous debate among members of the White House coronavirus task force — including its newest member, Dr. Scott W. Atlas, a frequent Fox News guest and a special adviser to President Trump.
“We all signed off on it, the docs, before it ever got to a place where the political leadership would have, you know, even seen it, and this document was approved by the task force by consensus,” Dr. Giroir said. “There was no weight on the scales by the president or the vice president or Secretary Azar,” he added, referring to Alex M. Azar II, the secretary of health and human services.
Regardless of who is responsible, the shift is highly significant, running counter to scientific evidence that people without symptoms could be the most prolific spreaders of the coronavirus. And it comes at a very precarious moment. Hundreds of thousands of college and K-12 students are heading back to campus, and broad testing regimens are central to many of their schools’ plans. Businesses are reopening, and scientists inside and outside the administration are growing concerned about political interference in scientific decisions.
Democratic governors who were weighing how to keep the virus contained as their economies and schools come to life said limiting testing for asymptomatic citizens would make the task impossible.
“The only plausible rationale,” Gov. Andrew M. Cuomo of New York told reporters in a conference call from Albany, N.Y., “is that they want fewer people taking tests, because as the president has said, if we don’t take tests, you won’t know the number of people who are Covid-positive.”
Over the weekend, the Food and Drug Administration, under pressure from Mr. Trump, gave emergency approval to expand the use of antibody-rich blood plasma to treat Covid-19 patients. The move came just days after scientists, including Dr. Anthony S. Fauci, the nation’s top infectious disease expert, and Dr. Francis S. Collins, the director of the National Institutes of Health, intervened to stop the practice because of lack of evidence that it worked.
The move echoed a decision by the Food and Drug Administration to grant an emergency use waiver for hydroxychloroquine, a malaria drug repeatedly sold by Mr. Trump as a treatment for Covid-19. The agency revoked the waiver in June, when clinical trials suggested the drug’s risks outweighed any possible benefits.
The testing shift, experts say, was a far more puzzling reversal. Dr. Giroir said the move was “discussed extensively by” members of the White House coronavirus task force, and he named Dr. Redfield, Dr. Atlas, Dr. Fauci and Dr. Stephen M. Hahn, the commissioner of food and drugs. Notably, he did not name Dr. Deborah L. Birx, the White House coronavirus response coordinator. But he said Dr. Fauci was among those who had “signed off.”
In a brief interview, Dr. Fauci said he had seen an early iteration of the guidelines and did not object. But the final debate over the revisions took place at a task force meeting on Thursday, when Dr. Fauci was having surgery under general anesthesia to remove a polyp on his vocal cord. In retrospect, he said, he now had “some concerns” about advising people against getting tested, because the virus could be spread through asymptomatic contact.
“My concern is that it will be misinterpreted,” Dr. Fauci said.
The newest version of the C.D.C. guidelines, posted on Monday, amended the agency’s guidance to say that people who had been in close contact with an infected individual — typically defined as being within six feet of a person with the coronavirus and for at least 15 minutes — “do not necessarily need a test” if they do not have symptoms.
Exceptions might be made for “vulnerable” individuals, the agency noted, or if health care providers or state or local public health officials recommended testing.
Dr. Giroir said the new recommendation matched existing guidance for hospital workers and others in frontline jobs who have “close exposures” to people infected with the coronavirus. Such workers are advised to take proper precautions, like wearing masks, socially distancing, washing their hands frequently and monitoring themselves for symptoms.
He argued that testing those exposed to the virus was of little utility, because tests capture only a single point in time, and that the results could give people a false sense of security.
“A negative test on Day 2 doesn’t mean you’re negative. So what is the value of that?” Dr. Giroir asked, adding, “It doesn’t mean on Day 4 you can go out and visit Grandma or on Day 6 go out without a mask on in school.”
The guidelines come amid growing concern that the C.D.C., the agency charged with tracking and fighting outbreaks of infectious disease, is being sidelined by its parent agency, the Department of Health and Human Services, and the White House. Under ordinary circumstances, administering public health advice to the nation would fall squarely within the C.D.C.’s portfolio.
Experts have called the revisions alarming and dangerous, noting that the United States needs more testing, not less. And they have expressed deep concern that the C.D.C. is posting guidelines that its own officials did not author. A former C.D.C. director, Dr. Thomas R. Frieden, railed against the move on Twitter on Wednesday:
Dr. Tom Frieden
@DrTomFrieden
Two unexplained, inexplicable, probably indefensible changes, likely imposed on CDC’s website. * Dammit, if you come from a place with lots of Covid, quarantine for 14 days * If you’re a contact, get tested. If +, we can trace your contacts and stop chains of spread. A sad day.
Later, in an interview, Dr. Frieden elaborated. He noted that the C.D.C. had recently dropped its recommendation that people quarantine for 14 days after traveling from an area with a high number of cases to one where the virus was less prevalent. And he reiterated that testing the contacts of those infected was an important means of curbing the spread of the virus.
“We don’t know the best protocol for testing of contacts: Should you test all contacts? That’s the kind of study that frankly needs to get done,” Dr. Frieden said. But absent the answer to that question, he added, “I certainly wouldn’t say, ‘Don’t test contacts.’”
Democrats, including Speaker Nancy Pelosi and two governors — Mr. Cuomo and Gavin Newsom of California — were outraged by the changes. Mr. Newsom said California would not follow the new guidelines, and Mr. Cuomo blamed Mr. Trump.
Representative Frank Pallone Jr. of New Jersey, a Democrat and the chairman of the House Energy and Commerce Committee, also chimed in on Twitter: “The Trump Admin has a lot of explaining to do. #COVID19 testing is essential to stopping the spread of the pandemic. I’m concerned that CDC is once again caving to political pressure. This simply cannot stand.”
Mr. Trump has suggested that the nation should do less testing, arguing that administering more tests was driving up case numbers and making the United States look bad. But experts say the true measure of the pandemic is not case numbers but test positivity rates — the percentage of tests coming back positive.
As Dr. Giroir denied that politics was involved, he encouraged the continued testing of asymptomatic people for surveillance purposes — to determine the prevalence of the virus in a given community — and said such “baseline surveillance testing” would still be appropriate in schools and on college campuses.
“We’re trying to do appropriate testing, not less testing,” he said.
Still, the revisions left many public health officials scratching their heads. They might have made sense when the United States was experiencing a shortage of tests, some experts said, but that no longer appears to be the case. Dr. Frieden, however, said it was possible the administration was trying to conserve testing in case of another surge.
“The problem is we have too many cases, so there is basically no way to keep up the testing if you have a huge outbreak,” he said.
Jennifer Nuzzo, an epidemiologist at Johns Hopkins Bloomberg School of Public Health, said she was “not as up in arms about the content of the guidelines” as she was about the idea that the C.D.C.’s own experts did not write them — and that C.D.C. officials were referring all questions about them to the health department in Washington.
“These guidelines are clearly controversial, and many are calling on C.D.C. to explain its rationale for them, but C.D.C. is unable to comment,” she said in an email. “This is really dangerous precedent, and I fear it will erode public trust in C.D.C.”
Walmart files plans for standalone clinic in Florida
Walmart plans to open a 6,500-square-foot standalone clinic in Middleburg, Fla., according to the Jacksonville Record & Observer, which cited plans filed with the local water management district.
The new clinic is part of the expansion Walmart Health announced July 22. The new health center will offer primary care, urgent care, labs, imagining, counseling, optical and hearing services, according to the report. A timeline for when the clinic will open has not been released.
In addition to expanding into Florida, Walmart Health is also planning to open a few clinics in the Chicago market. The company already has freestanding health centers in Georgia and Arkansas.
HENRY KOTULA 