• The Star Staff

FDA’s emergency approval of blood plasma is now on hold


By Noah Weiland, Sharon Lafraniere and Sheri Fink


Last week, just as the Food and Drug Administration was preparing to issue an emergency authorization for blood plasma as a COVID-19 treatment, a group of top federal health officials including Dr. Francis Collins and Dr. Anthony Fauci intervened, arguing that emerging data on the treatment was too weak, according to two senior administration officials.


The authorization is on hold for now as more data is reviewed, according to H. Clifford Lane, the clinical director at the National Institute of Allergy and Infectious Diseases. An emergency approval could still be issued in the near future, he said.


Donated by people who have survived the disease, antibody-rich plasma is considered safe. President Donald Trump has hailed it as a “beautiful ingredient” in the veins of people who have survived COVID-19.


But clinical trials have not proved whether plasma can help people fighting the coronavirus.


Several top health officials — led by Collins, the director of the National Institutes of Health; Fauci, the government’s top infectious disease expert; and Lane — urged their colleagues last week to hold off, citing recent data from the country’s largest plasma study, run by the Mayo Clinic. They thought the study’s data to date was not strong enough to warrant an emergency approval.


“The three of us are pretty aligned on the importance of robust data through randomized control trials, and that a pandemic does not change that,” Lane said in an interview Tuesday.


The drafted emergency authorization leaned on the history of plasma’s use in other disease outbreaks and on animal research and a spate of plasma studies, including the Mayo Clinic’s program, which has given infusions to more than 66,000 COVID-19 patients thanks to financing from the federal government.


An FDA spokeswoman declined to comment.


Plasma, the pale yellow liquid leftover after blood is stripped of its red and white cells, has been the subject of months of intense enthusiasm from scientists, celebrities and Trump, part of the administration’s push for coronavirus treatments as a stopgap while pharmaceutical companies race to complete dozens of clinical trials for coronavirus vaccines.


Emergency authorizations, which do not require the same level of evidence as a full FDA approval would, have been a fraught subject for the government during the pandemic. The agency gave one to the malaria drugs hydroxychloroquine and chloroquine only to rescind it months later after the drugs were found to be ineffective against the coronavirus, and potentially harmful. An emergency authorization for blood plasma would most likely ease the clerical burdens on hospitals in conducting infusions.


Senior health officials have privately expressed concern about the rapid growth of the Mayo program and the perceived rush to declare plasma effective without the affirmation of results from randomized trials, which scientists have long relied on as the gold standard of evidence. Skyrocketing enrollment in the program has prompted a debate among researchers about what kind of empirical certainty is needed in treating patients in a public health emergency.


An emergency approval now would “change the way people view trials,” said Dr. Mila B. Ortigoza, an infectious disease specialist at NYU Langone Health who started a trial with colleagues at Montefiore Medical Center.


“We want to make sure that when we say it works, we are confident, with indisputable evidence,” she said. “We’re dealing with patients’ lives here.”


Unlike the malaria drugs, plasma, which has been used since the 1890s to treat infectious diseases, has earned the attention of a highly credentialed community of microbiologists and immunologists eager to prove its usefulness. The Mayo Clinic has already published analysis on tens of thousands of patients in its expanded access program showing that plasma is safe.


The most recent batch of data from the program included more than 35,000 COVID-19 patients, many of them in intensive care and on ventilators, and suggested that plasma administered within three days of a diagnosis reduced mortality rates. When calculated a month after the infusions, the death rate of patients who received plasma within three days of diagnosis was lower (21.6%) than it was for those who received plasma later (26.7%).


But the study did not have a control group of patients given a placebo to compare with those given plasma, making it difficult for scientists to assess whether the treatment really worked. And given the limited supply of plasma, it is not clear how realistic treating patients within three days of diagnosis would be.


Statisticians at the FDA are now examining the Mayo data to better understand what factors other than the treatment might have influenced patient responses, such as higher-quality care in the hospital, Lane said.


A research team from Houston Methodist hospitals also published preliminary results from a plasma trial last week. Their study of hospitalized COVID-19 patients in the American Journal of Pathology reported that a group of 136 patients who received the treatment were more likely to be alive four weeks later compared with 251 patients who did not receive it. That study found a statistically significant benefit only when patients were treated within three days of admission and when the plasma contained a high concentration of antibodies.


The Houston study was not randomized, meaning that all of the patients enrolled received the treatment and none received a placebo. (The researchers later compared their outcomes to records from other COVID-19 patients who were not in the study but were matched to be similar to them.)


A surge in cases in Texas this summer quickly brought the hospital system to its enrollment cap, and doctors there have not been able to provide the experimental treatment since mid-July. If the FDA gave an emergency authorization, doctors at the hospital could possibly begin administering it again, said Dr. Eric Salazar, the study’s principal investigator.


But an emergency authorization could have the unintended effect of making it harder for rigorous clinical trials to definitively show whether plasma works. Scientists have struggled to recruit patients for randomized trials, as many patients and their doctors — knowing they could get the treatment under the Mayo program — have been unwilling to risk receiving a placebo.


Last month, one such trial in the Netherlands was stopped when researchers realized that patients given plasma showed no difference in mortality, length of hospital stay or disease severity compared with those given a placebo. Most of the patients had already developed their own antibodies by the time they entered the study, the researchers noted.

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