Convalescent plasma misses the mark in phase 2 trial

Hopes that antibody-laden plasma taken from recovered COVID-19 patients could lessen the severity of the disease in others have taken a knock.

The 464-subject PLACID trial – carried out in India – found that the use of so-called convalescent plasma was unable to prevent progression to severe disease or reduce mortality in people hospitalised with moderate COVID-19.

The finding comes after the US issued an Emergency Use Authorisation (EUA) for convalescent plasma in August, despite opposition from some medical experts who said it was premature as the safety and efficacy of the approach had not been established in human testing.

The approval also came amid a spat between the FDA and President Trump, who had accused the agency of impeding progress on coronavirus therapies, and was followed by an embarrassing data gaffe by agency head Stephen Hahn during a press conference announcing the EUA.

Some countries, including the UK, have been collecting and stockpiling convalescent plasma in the hope that it can be deployed quickly to patients if it proves effective in clinical trials.

Now however, it looks like those who advised caution may have had good cause. While it’s worth pointing out that PLACID was an open-label rather than a double-blind study, the trial investigators claim it “approximates convalescent plasma use in real-life settings”.

Studies have shown convalescent plasma from COVID-19 survivors contains antibodies with potent antiviral activity, but there are a lot of unanswered questions about use in patients, including the levels of antibodies needed to be effective, the timing of plasma donation and treatment and the types of patents most likely to respond.

Writing in the British Medical Journal, the authors – led by Anup Agarwal of the Indian Council of Medical Research in New Delhi – say that while prior studies have suggested that convalescent plasma can reduce viral load, the time patients need to spend in hospital, and death rates, that wasn’t the case in their trial.

The primary outcome – progression to severe disease or all-cause mortality at 28 days – was seen in 19% of patients receiving plasma plus standard supportive care, compared to 18% of those in the control arm on supportive care alone.

There were some beneficial effects, including shorter times to resolution of symptoms like shortness of breath and fatigue, but plasma therapy didn’t seem to improve biomarkers for the runaway inflammation that is associated with COVID-19 requiring hospitalisation.

In an editorial accompanying the study, Elizabeth Pathak of the Women’s Institute for Independent Social Enquiry in Maryland, US, said that as the study wasn’t blinded, it was possible that patients who knew they were getting plasma might expect to feel better, and so reported improvements in symptoms.

She also points out that convalescent plasma isn’t without risks – in fact, the FDA specifically warns about the risks of blood clots with the therapy, particularly in older patients and those with cardiovascular risk factors.

Other studies of convalescent plasma are still ongoing, including the UK RECOVERY trial which has already shown the benefits of the steroid dexamethasone in adults with COVID-19, as well as the failure of the antiviral combination lopinavir-ritonavir.

Convalescent plasma is one of three other therapies being put through their places in the study.

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Industry group says FDA botched COVID-19 convalescent plasma guidance

Already under fire for what some view as a premature authorisation of convalescent plasma for COVID-19, the FDA is now being accused of a blunder that could render current supplies unusable.

Bioindustry association MichBio says the FDA’s labelling requirements for COVID-19 convalescent plasma (CCP) – which were published alongside the emergency use authorisation – could lead to “hundreds, if not thousands, of in-date, ready to transfuse CCP units across the country being rendered unusable.”

The problem lies with the requirement that each unit of plasma includes information on the concentration of antibody titres, something which wasn’t required for CCP units collected ahead of the EUA on 23 August.

MichBio adds that while it may be possible to relabel some of these units appropriately, that represents “a monumental undertaking by blood centres, and any transfusion services that have units in-house are unable to relabel them.”

Convalescent plasma treatment involves giving COVID-19 patients antibody-rich blood plasma from people who have already recovered from the disease, and has already been used in 70,000 people in the US under an Expanded Access Programme launched in April.

Two US lawmakers – Reps Debbie Dingell (D-MI) and Fred Upton (R-MI) – have already picked up on the issue and have written to FDA Commissioner Stephen Hahn, asking that the FDA “take prompt action to ensure that these requirements do not unduly inhibit patient access to convalescent plasma.”

They say that delays to treatment with CCP “could have an impact on patient outcomes, with preprint data indicating that time to transfusion is a key factor correlated with lessening the severity or shortening the length of illness.”

The preprint data referred to is a Mayo Clinic study used to support the EUA based on data taken from patients treated with plasma under the Expanded Access Programme.

It’s another embarrassment for the FDA, coming after Commissioner Hahn was forced to back-pedal on statements he made during a press conference to announce the EUA last Sunday, particularly that the use of CCP could improve survival in COVID-19 patients by 35%.

“What that means is…in 100 people who are sick with COVID-19, 35 would have been saved because of the administration of plasma,” said Hahn.

As it stands, only one or two people out of 100 would be expected to die if they had COVID-19, so the claim makes little sense.

Moreover, the figure is a misinterpretation of data from the Mayo study, which compared plasma with high antibody titres to plasma with low titres, not plasma versus no plasma, and revealed a relative rather than absolute risk reduction – as conceded by Dr Hahn later.

Criticism of the FDA is coming from many sides, including influential Scripps Research scientist Eric Topol, who wants the FDA to hold a second press conference to correct the mis-communication, and believes the credibility of the agency is at an all-time low.

The overblown claims also led to accusations that the FDA was playing politics, and pandering to President Trump’s desire to show evidence of progress on COVID-19 as the US election looms, a claim that Dr Hahn also denies, saying “the decision was made by FDA career scientists based on data submitted a few weeks ago.”

Nevertheless, the labeling controversy further undermines that credibility and according to MichBio “if not rapidly corrected, will lead to significant delays in transfusion of patients across the country for the foreseeable future, or, put transfusion services licenses at risk for wilfully violating FDA requirements.”

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FDA’s emergency authorization for convalescent plasma in Covid-19 sparks controversy

While the emergency use authorization granted Sunday was not seen as scientifically unwarranted, it drew concerns from some experts that it could hinder enrollment in clinical trials, while the timing and circumstances of the FDA’s move fueled suspicions that political pressure – rather than science and data alone – may have played a role.

Trump launches baseless attack on FDA; agency controversially authorizes plasma treatment for Covid-19

Over the weekend, Trump called the agency, without evidence, part of a “deep state” that was slow-walking vaccines and drugs for Covid-19. The next day, the agency authorized convalescent plasma despite having turned it down shortly before due to insufficient evidence.

COVID plasma treatment gets emergency license from FDA after Trump criticism

The FDA has allowed a blood plasma treatment for COVID-19 to be administered under an Emergency Use license – but some have decried the move as a “political stunt” as president Trump accuses the agency of impeding progress on coronavirus therapies.

The convalescent plasma treatment involves giving COVID patients antibody-rich blood plasma from people who have already recovered from the disease.

It has already been used on over 70,000 people in the US under an Expanded Access Program launched in April, which opened up use to patients who were seriously ill or involved in clinical trials, and now the agency has given it an Emergency Use License while clinical trials remain ongoing.

The FDA said that, based on early data from an analysis of 20,000 patients who received this treatment, it is “reasonable to believe” that COVID-19 convalescent plasma may be effective in lessening the severity of the illness in some hospitalised patients. 

The agency added that the known and potential benefits of the product when used to treat COVID-19 outweigh the risks, and that there are no adequate, approved, and available alternative treatments.

But experts have questioned whether there is really enough data to show that the treatment is safe and effective – especially as the announcement came only a day after president Trump accused the FDA of deliberately impeding progress on COVID-19 treatment and vaccines until after the US election on 3 November.

“Convalescent plasma may have some efficacy, but we need to have definitive data and tonight’s EUA was clearly a political stunt,” Jonathan Reiner, a professor of medicine at George Washington University, said on Twitter.

Meanwhile, the Infectious Diseases Society of America said in a statement that “we lack the randomised controlled trial data we need to better understand [convalescent plasma’s] utility in COVID-19 treatment”.

However, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research said the agency was “comfortable” with the data and that they “continue to see no concerning safety signals.

“I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives,” added  FDA Commissioner Stephen Hahn. “We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus.

“At the same time, we will continue to work with researchers to continue randomised clinical trials to study the safety and effectiveness of convalescent plasma in treating patients.”

In April a group of companies that specialise in plasma-derived drugs announced that they will pool their resources to try to develop an “unbranded” hyperimmune immunoglobulin drug for SARS-CoV-2, the virus that causes COVID-19.

Led by Takeda and CSL Behring, the consortium also includes Biotest, BPL Group, LFB and Octapharma.

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Report: FDA halted move to authorize convalescent plasma for Covid-19 over evidence concerns

The New York Times reported that the FDA was prepared to issue an emergency use authorization for the treatment last week, but NIH Director Francis Collins and NIAID Director Anthony Fauci intervened, arguing that data were too weak.