Convalescent plasma for Covid-19 may not be as effective as hoped

 Here's a recent article from the New England Journal of Medicine: they conclude that treatment of Covid-19 patients with convalescent plasma is no better than a placebo treatment (for a group of seriously ill patients with over a 10% mortality rate).

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia

by Ventura A. Simonovich, M.D., Leandro D. Burgos Pratx, M.D., Paula Scibona, M.D., María V. Beruto, M.D., Marcelo G. Vallone, M.D., Carolina Vázquez, M.D., Nadia Savoy, M.D., Diego H. Giunta, M.D., M.P.H., Ph.D., Lucía G. Pérez, M.D., Marisa del L. Sánchez, M.D., Andrea Vanesa Gamarnik, Ph.D., Diego S. Ojeda, Ph.D., et al., for the PlasmAr Study Group

RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups.

CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. 

HT: Irene Wapnir

Paying for plasma to be legal in Alberta

 Reason magazine has the story:

Canada Inches Closer to Allowing More People To Be Paid for Plasma--For too long, our northern neighbors have depended on plasma imported from the U.S. to meet demand. With the passage of new legislation in Alberta, this may change.  by LIZ WOLFE 

"Albertans will soon be able to receive payment for their blood and plasma donations. Bill 204, the Voluntary Blood Donations Repeal Act, was introduced by Tany Yao, a member of the legislative assembly for Alberta's provincial government, and passed in the legislature this week. It must now get royal assent—a mere formality—for it to become law. The bill overturns a 2017 prohibition on paid plasma, and will allow private companies to pay plasma donors for their efforts. If they so choose, people will still be able to donate blood and plasma without receiving compensation via Canadian Blood Services.

...

"United Nurses of Alberta's president Heather Smith told Global News that "the government is putting its ideology and desire to support profiteers above what is actually safe for Albertans and Canadians." Elsewhere she said that "donating blood should not be viewed as a business venture."

HT: Peter Jaworski

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

There is starting to be an empirical literature associated with payments for socially productive activities, such as participating in challenge trials of vaccines, donating plasma, etc.

Here's a blog post in the Medical Ethics blog of the Journal of Medical Ethics:

Is it acceptable to pay nothing or little to challenge trial participants?  By Sandro Ambuehl, Axel Ockenfels and Alvin E Roth.   October 30, 2020

Here's a paragraph (with some links).:

"we hope that the debates about payments in medical research, and on other transactions subject to restrictions on payments such as blood plasma donations, will converge as empirical results accumulate. To date, there is empirical evidence on the underlying motivations for volunteering, on the impact of high payment on human risk taking, on decision quality and well-being, on the signal value of small payments, on strategies to evade regulation, and on the general public’s assessment of appropriate activities and  payments. Moreover, there are studies that document biases affecting normative judgment in general, and biases affecting paternalistic restrictions and moral intuitions in particular.

***********

This blog post was written in connection with our paper in the JME:

Payment in challenge studies from an economics perspective 

by Sandro Ambuehl, Axel Ockenfels, and Alvin E. Roth

published online early, Oct 28, 2020. http://dx.doi.org/10.1136/medethics-2020-

An open letter to Canadian health authorities on laws against compensating Canadian plasma donors

 The letter is available on a website called Donation Ethics: Ethicists and Economists for Ethical Donation-Compensation Practices  organized by Peter M. Jaworski and  David Faraci. (I am among the signers.)

"Ethicists and Economists express concerns about banning compensation for plasma donors with regards to ensuring the security of a safe Immune Globulin Product Supply.

"Submission to the Expert Panel on Immune Globulin Product Supply and Related Impacts in Canada

"INTRODUCTION

We are professional ethicists in the fields of medical ethics, business ethics, and/or normative ethics, and academic economists who study how incentives and other mechanisms affect individual behaviour. We all share the goal of improving social welfare.

"The Provinces of Québec (1994),1 Ontario (2014),2 and Alberta (2017)3 have passed Voluntary Blood Donation Acts or their equivalents that prohibit, amongst other things, compensation for plasma donations for purposes of further processing into plasma-derived medicinal products (hereafter: “PDMPs”), like Immune Globulin (hereafter: “Ig”). Currently, the Nova Scotia legislature is debating a Voluntary Blood Donations Act,4 and the British Columbia government has suggested that it is interested in pursuing similar legislation.5

...

"CONCLUSION

"In our view, none of the moral objections to the compensatory model are persuasive. Furthermore, there is a strong moral presumption against standing in the way of a model that is the most likely to promote security not only of Canada’s supply of PDMPs, including Ig, but also of the global supply. We urge Québec, Ontario, and Alberta to reconsider the Acts currently prohibiting compensation in their provinces.

"Finally, we note that well-informed opponents of the compensatory model should not suggest that PDMPs, including Ig, made with compensated donors are riskier or less safe than PDMPs, including Ig, made with uncompensated donors. This presumption may be harmful to patients."

Convalescent plasma continues to be used for treatment of covid-19, but demand is flat

 The WSJ has the story:

Wanted in Covid-19 Fight: ‘Superdonors’ of Convalescent Plasma--Blood banks and researchers are mobilizing to find recovered Covid-19 patients who have high levels of antibodies and are willing to donate regularly   By Amy Dockser Marcus

"Blood banks and researchers are mobilizing to find recovered Covid-19 patients who could be blood plasma “superdonors,” people who have high levels of antibodies against the disease and are willing to donate regularly.

"The hunt has intensified in the past month, after the Food and Drug Administration authorized the use of convalescent plasma, derived from patients who have survived the virus, as a potential therapy for hospitalized patients.

...

"Right now, demand for plasma overall is flat, said Dr. Claudia Cohn, chief medical officer for AABB, a group representing the transfusion medicine and cellular therapy community. She said it could reflect reservations about the strength of existing data, the waning of the pandemic in certain areas of the country, or concerns that the authorization was issued under political pressure from the White House—a suggestion the FDA has pushed back on but that continues to generate debate.

"Doctors said an expected upturn in demand for convalescent plasma didn’t materialize after the authorization, although they are prepared for one should infections surge later this year."

Plasma in Canada, and repugnant transactions--a podcast interview

 I was recently interviewed by Kate van der Meer, a Canadian patient affected by the plasma shortage of 2019. Her experience inspired her to look deeper into the plasma supply chain and raise awareness to the negative implications of the Voluntary Blood Donations Act. Part of this awareness campaign is the Plasma For Life Podcast Series, of which this interview is a part. 

(Her website is  www.plasmaforlife.org.)

.

Is convalescent plasma useful for treating covid-19?

The reported results on convalescent plasma are so far still quite incomplete, and mixed.  If I had to summarize, I'd say that a growing body of evidence suggests that treating early stage (e.g. just hospitalized) covid-19 patients increases and speeds the chance of recovery, while there is little convincing evidence that convalescent plasma helps more severely ill patients who have begun to have serious complications.

Here is a recent WSJ article:

Convalescent Plasma Reduced Death Rate Among Covid-19 Patients, Study Data Signals

Hospitalized patients who got earlier transfusions of blood plasma rich in antibodies to the coronavirus show a lower mortality rate

By Amy Dockser Marcus

"Hospitalized Covid-19 patients who received transfusions of blood plasma rich with antibodies from recovered patients reduced their mortality rate by about 50%, according to researchers running a large national study.

...

"The researchers said they saw signs that the treatment might be working in patients who received high levels of antibodies in plasma early in the course of their illness. They based their conclusions on an analysis of about 3,000 patients."

************

Here's a recent paper in JAMA on a very small randomized trial in China that doesn't find statistically significant effects on patients who 

August 4, 2020

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Ling Li, MD, PhD; Wei Zhang, MD; Yu Hu, MD, PhD; Xunliang Tong, MD, PhD; Shangen Zheng, MD; Juntao Yang, PhD; Yujie Kong, MD; Lili Ren, PhD; Qing Wei, MD; Heng Mei, MD, PhD; Caiying Hu, MD; Cuihua Tao, MD; Ru Yang, MD; Jue Wang, MD; Yongpei Yu, PhD; Yong Guo, PhD; Xiaoxiong Wu, MD; Zhihua Xu, MD; Li Zeng, MD; Nian Xiong, MD, PhD; Lifeng Chen, MD; Juan Wang, MD; Ning Man, MD; Yu Liu, PhD; Haixia Xu, MD; E. Deng, MS; Xuejun Zhang, MS; Chenyue Li, MD; Conghui Wang, PhD; Shisheng Su, PhD; Linqi Zhang, PhD; Jianwei Wang, PhD; Yanyun Wu, MD, PhD; Zhong Liu, MD, PhD

  JAMA. 2020; 324(5):460-470. doi: 10.1001/jama.2020.10044

Abstract: This randomized trial compares the effects of convalescent plasma therapy with standard care vs standard care alone on time to clinical improvement among patients with severe or life-threatening COVID-19 disease in China.

"Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference."

**********

My last donation had high enough antibodies to qualify me for another: I hope these are going to patients for whom they will be useful.

More on plasma, payments, and convalescent plasma

Peter Jaworski gives some more reasons that countries should legalize compensation to plasma donors, rather than buying their plasma products from the U.S.

In Reason:
Americans Get Paid To Donate Plasma. Everyone Else Should Too
Our secret weapon against COVID-19 could be cold, hard cash.  7.2.2020

"American dominance in the plasma market is explained by one simple fact: In America, it is legal and commonplace to pay people to give plasma. Millions of Americans regularly give plasma in exchange for $30 to $50 per donation. The average American donor gives 21.4 times per year, with a per capita collection volume of 113 liters of plasma per 1,000 people. If you add plasma obtained from Germany, Austria, Hungary, and Czechia—the other places where a form of compensation (typically capped at 25 euros, intended only to cover expenses) is offered—paid plasma accounts for a staggering 89 percent of all the plasma used to make plasma therapies for the whole world. Just five countries account for nine-tenths of the world's plasma.
...
"Donor recruitment and retention, staffing, plus marketing costs, combine to make the collection of unpaid plasma two to four times more expensive than just giving money to the donors.
...
"[bans on payment were partly] motivated by the concern that payment attracted people from lower socioeconomic rungs of the economic ladder who are more likely to be carriers of HIV, hepatitis C, and other transfusion-transmissible infections.

"But those concerns no longer apply, partly due to significant improvements in testing technology since the 1970s when the WHO first recommended not paying blood and plasma donors. This improvement in testing happens to form the backbone of arguments among advocates of eliminating restrictions on blood and plasma donation by gay men, which currently require three months of celibacy per the Food and Drug Administration's revised guidance issued this April. But improvements in testing alone are not the reason why plasma for plasma therapies should be considered categorically different from blood and plasma used for transfusions; it is manufacturers' ability to use virus removal and inactivation techniques that marks the stark difference.

"In the 1980s, we discovered that heat treatment was effective against HIV. Much like how washing your hands with soap destroys the coronavirus, use of solvents and detergents are effective against lipid-enveloped viruses, including hepatitis C and HIV. Nanofiltration ensures that only molecules of a certain size—the proteins we want—get through, preventing larger molecules from passing into the plasma pool. Most American paid plasma collection centers are also International Quality Plasma Program (IQPP) certified. This voluntary standard, issued by the Plasma Protein Therapeutics Association, involves additional safety steps including the requirement that any donor's first donation be placed on hold, only to be released with the second donation from the same donor. This holding step gives us an opportunity to test the same plasma twice, avoiding the rare possibility of a virus being within the window period where it cannot be detected. This hold means that if you give plasma once and don't go back, your plasma will be discarded."
**********

With convalescent plasma donation,  the safety check involved in sequestering the first donation until the second one is also tested for infection is not the only set of tests.  For each donation there is also a measurement of how much Covid-19 antibody (IgG) is present, and if it is enough to be therapeutic. So, for example, after each donation I have to wait for those results to find out if I'll be invited to donate again. (So far, at each visit I give a bit over 800ml of plasma, and that donation is divided into four units of 200ml. My understanding is that my units have so far all been administered to hospitalized Covid-19 patients in Fresno and San Jose.)

Nicola Lacetera, on The Ethics and Economics of Paying Plasma Donors

Nicola Lacetera is among the leaders in studying public views about compensating donors of various sorts. Here he discusses the plasma supply, which is particularly timely given the growing availability of convalescent plasma for Covid-19. (30 minutes)

Peter Jaworski on The Case for Voluntary Remunerated Plasma Collections

Peter Jaworski makes the case for allowing compensation of plasma donors in the wealthy nations of the British Commonwealth:

Bloody Well Pay Them: The Case for Voluntary Remunerated Plasma Collections
BY PETER JAWORSKI JUNE 14, 2020

Here's the executive summary ( a long summary of a long paper):

"•Blood plasma is used in a wide, and growing, range of life-saving therapies. It is now being trialled to treat Covid-19, including by the United Kingdom’s National Health Service.

• There are significant global shortages of blood plasma. Demand is growing at a rate of 6-10% per year. Three-quarters of people do not have access to the appropriate plasma therapy, largely outside of developed countries.
• Shortages are significantly exacerbated by the World Health Organisation’s policy — adopted by the United Kingdom, Australia, New Zealand and some Canadian provinces — to rely exclusively on Voluntary Non-Remunerated Blood Donations (VNRBD).
• The United Kingdom imports 100% of its supply of blood plasma, Canada (84%), Australia (52%), and New Zealand (13%). They are increasingly dependent on imports for blood plasma from countries that remunerate donors. This inflates the global blood plasma price, making it unaffordable for low to middle income countries.
• The United States, which allows remuneration of donors, is responsible for 70% of the global supply of plasma. Together with other countries that permit a form of payment for plasma donations — including Germany, Austria, Hungary, and Czechia —they account for nearly 90% of the total supply. The dependence on a small number of countries is a serious health security threat.
• Non-remunerated donations are estimated to be 2-4 times more expensive than remunerated collections, because of the expense of recruiting and retaining donors, including through marketing. Australia, for example, could save $200 million annually by importing all blood plasma.
• There are significant global shortages of plasma therapies. The growing global demand cannot be met without remuneration.
• The evidence is clear that remunerating individuals for blood plasma donations is safe, would ensure a secure supply of plasma, does not discourage non-remunerated blood donations, and would provide significant patient benefits, including peace of mind.
• In order to ensure a safe, secure, and sufficient supply of plasma therapies, the United Kingdom, Canada, Australia, and New Zealand should adopt Voluntary Remunerated Plasma Collections (VRPC):
• VRPC means individuals are paid, in cash or in-kind, to give plasma of their own free will. It also means collections using modern deferral and testing techniques, such as deferring higher-risk donors and advanced viral detection tests.
• VRPC would allow the Canzuk countries to at the very least become self-sufficient, and potentially contribute to the humanitarian goal of increasing the global supply of blood plasma for low to middle income countries."

Here's a description of the historical setting:

"On June 11, 2009, the World Health Organization (WHO) issued “The Melbourne Declaration on 100% Voluntary Non-Remunerated Donation of Blood and Blood Components.”  The Declaration was a re-commitment to, what they call, “Voluntary Non-Remunerated Blood Donations” or VNRBD,” as well as to World Blood Donor Day, celebrated every June 14th.  The Declaration set a target date for achieving 100% VNRBD in safe, secure, and sufficient blood and blood products, including plasma-derived medicinal products. That target date was 2020.
...
"This year will end without a sufficient supply of plasma based on 100% non-remunerated plasma collections, neither will 2030. With each passing year from 2009 to the present, the world has moved further from that target, and closer to being nearly entirely dependent on the United States."

*******

Before publishing the paper, Jaworski solicited some supportive quotes to use as blurbs.  Here's mine:

Nobel Prize winning economist Alvin Roth says of the current over-reliance on the US’ paid donor market:
“I find confusing the position of some countries that compensating domestic plasma donors is immoral, but filling the resulting shortage by purchasing plasma from the U.S. is ok.”

Convalescent plasma collection ramps up

Here's a story from the WSJ:
Blood Banks, Pharma Join Microsoft to Sign Up Covid-19 Survivors for Plasma

"A coalition of research institutions, blood banks, drug companies and recovered Covid-19 patients is working to overcome a major challenge in developing new therapies based on survivors’ blood plasma: a shortage of donors.

"With a campaign launched Tuesday called The Fight Is In Us, the group aims to get tens of thousands of people who have recovered from Covid-19 infections to donate plasma using a self-screening tool developed by Microsoft Corp. MSFT -0.17%

"So far nearly 15,000 seriously ill Covid-19 patients have received plasma transfusions in an emergency, expanded-access program authorized by the Food and Drug Administration
...
"The Red Cross has collected plasma from 4,000 recovered Covid-19 donors to date through its website RedCrossBlood.org/plasma4covid, according to a spokeswoman. She said the organization supports the efforts of the coalition but didn’t join it. “At this time, the Red Cross is fortunate to be able to meet the needs of our hospital partners,” she said. “We also have the capacity to ramp up our supply if necessary.”
...
"Despite the unusual efforts to work together, for-profit companies in the coalition also continue to look for donors on their own through digital advertising and other online outreach, according to industry experts.

"Potential donors who go to the thefightisinus.org website start by using a self-screening tool. It asks if they were diagnosed for Covid-19 infection, have been symptom-free for more than 14 days, meet age and weight requirements for blood donation and have ever been diagnosed with HIV, hepatitis C or hepatitis B, which affects eligibility. The potential donors enter a ZIP Code and get a list of nearby donation centers.

"Peter Lee, corporate vice president at Microsoft, which developed the self-screening tool, said donors are currently directed to centers based on location. Coalition members are still discussing ways to determine how donors are allocated.
...
"Some plasma donors might prefer to give to a for-profit plasma company, where they might be reimbursed. Others might choose a local blood bank, where the plasma would be used right away for sick patients in a hospital and reimbursement isn’t offered
...
"In New York and other places affected early in the outbreak, many recovered patients have encountered long wait times to donate"

Blood and plasma: a brief history, from 1628

With all my discussion of convalescent plasma for Covid-19 this week*, here's a historical perspective on the technology and changes in medical practice since the discovery of blood circulation in 1628 that allows blood and plasma to be used in medicine.


A history of blood transfusion: a confluence of science—in peace, in war, and in the laboratory
by Kevin R. Loughlin
Hektoen International, Volume 12, Issue 2 – Spring 2020.

"Since 1628 when William Harvey discovered the circulation of blood, there had been hope that blood transfusion would be possible.
...
"After Harvey’s discovery, transfusion attempts began. In 1665 Richard Lower kept dogs alive by transfusing blood from other dogs.2 In 1667 French physician Jean Denys transfused nine ounces of blood from the carotid artery of a lamb into the vein of a young man. He continued the practice until the third patient so treated, died.3 Denys was sued by the wife of the deceased patient, who presumably died from a hemolytic reaction, but was exonerated. However, the French Parliament, the Royal Society, and the Catholic Church subsequently issued a general prohibition against transfusions.4

"It would not be until 1818 when transfusions were seriously considered again. A British obstetrician, James Blundell, performed a human blood transfusion in the setting of a postpartum hemorrhage.5 However, the debate over transfusions continued over the remainder of the nineteenth century. In 1849 C.H.F. Routh reviewed all the published transfusions to date and remarked in the Medical Times that of the 48 recorded cases, 18 had a fatal outcome and concluded that the mortality rate was unacceptably high.5 The next major advance in transfusion therapy would wait until the turn of the century.

"Karl Landsteiner was an Austrian physician and immunologist. While working at the University of Vienna, he became interested in blood serum work, specifically the factors that led to hemagglutination of red blood cells. This resulted in two landmark publications in 1900 and 1901 that described the evidence of blood groups that he named A, B, and C.6,7 These would later be modified to A, B, and O. Two years later, two of his colleagues, Alfred Von Decastelo and Adriano Sturli, would add a fourth blood type, AB.8,9 Landsteiner would be awarded the Nobel Prize in 1930 for his elucidation of the blood groups.

... in 1912, Doctor Roger Lee demonstrated that O blood could be given to a person of any blood type (universal donor) and that a person with AB blood could receive blood from any blood group (universal recipient).
...
"As blood transfusions became more widespread in medical practice, the concept of establishing blood banks became attractive. In the 1930s Bernard Fantus at Cook County Hospital20 and Carl W. Walter at Peter Bent Brigham Hospital started blood banks. In Boston, Walter’s efforts were viewed with such skepticism and disdain that his facility was relegated to a basement room at Harvard because some trustees thought the storage and use of blood was “immoral and unethical.”21 Fifteen years later he invented the plastic blood bag, which greatly facilitated transfusion therapy.21
...
"In 1940 Edwin Cohn developed ethanol fractionation, the process of breaking down plasma into component products. Albumin, gamma globulin, and fibrinogen were isolated to become available for clinical use.

"In 1944 dried plasma became available for the treatment of combat injuries. Component transfusion therapy became more widely used as the war progressed. The Red Cross concluded its World War II blood program in 1945 after 13 million pints had been collected.11

"In 1961 platelet concentrates became recognized for reducing mortality from hemorrhage in cancer patients. In 1964 plasmapheresis was introduced as a means of collecting plasma for fractionation. In 1971 Hepatitis B surface antigen (HbsAg) testing of donated blood began and in 1992 testing of donor blood for HIV-1 and HIV-2 antibodies commenced.
*************

*here's a recap of my earlier coronavirus posts relating to plasma this week:

Sunday, May 17, 2020

Cascades of convalescent plasma for Covid-19, and chains of exchanges, by Kominers, Pathak, Sönmez, and Ünver

Monday, May 18, 2020

Plasma and plasma products (such as antibodies) are a big business (and the U.S. dominates the international market)

Wednesday, May 20, 2020

Convalescent plasma collection and distribution

Convalescent plasma collection and distribution

Efforts to collect and distribute convalescent plasma from recovered Covid-19 patients are ramping up: there are lots of options.

I donate convalescent plasma at the Stanford Blood Center, in their program on
 CONVALESCENT PLASMA FROM RECOVERED COVID-19 PATIENTS
"This exciting initiative involves taking plasma donations from recovered COVID-19 patients and transfusing that plasma into critically ill COVID-19 patients in the hopes that the antibodies present in the donated plasma will help save the lives of the recipients."

Modern plasma collection is a one-arm process: the machine on my right in the photo alternates between taking blood and returning red blood cells through the same needle (in contrast to the old technology which had blood go out of a needle in one arm and red blood cells return through a needle in the other arm).

Collecting convalescent plasma is not regulated as a research activity, it is just ordinary plasma donation. However giving it to patients is done under FDA guidance, either as a research activity or as an emergency intervention for very ill patients:
Recommendations for Investigational COVID-19 Convalescent Plasma
"Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product."

There are three FDA-approved pathways right now by which convalescent plasma can be administered to patients.
"Pathways for Use of Investigational COVID-19 Convalescent Plasma:
1. Clinical Trials,
2.  Expanded Access "for patients with serious or immediately life-threatening COVID-19 disease"
3. Single Patient Emergency"

Here is a consortium of nonprofit blood centers, there's likely one near you if you're reading this in the States:
America's Blood Centers (association of independent blood centers)

• ABC Resources on COVID-19 and Convalescent Plasma
• America’s Blood Centers Partners with BARDA to Expand Collection of Convalescent Plasma for COVID-19 Patients

Here's the American Red Cross effort: Plasma Donations from Recovered COVID-19 Patients

My impression is that the nonprofit blood centers don't pay donors, but are able to sell plasma to customers, including the commercial plasma industry, as part of the thriving domestic and international market in plasma. (I blogged Monday about U.S. plasma exports, all over the world, including especially countries in which compensating donors is repugnant.)
*****************
The for-profit plasma industry (which compensates plasma donors) is represented by The Plasma Protein Therapeutics Association (PPTA)
Here's an announcement about their plans for Covid-19 antibodies:

1. CoVIg-19 Plasma Alliance Builds Strong Momentum Through Expanded Membership and Clinical Trial Collaboration

"The CoVIg-19 Plasma Alliance, an unprecedented plasma industry collaboration recently established to accelerate the development of a plasma-derived hyperimmune globulin therapy for COVID-19, is rapidly building momentum. Its membership has expanded globally to include 10 plasma companies, and now also includes global organizations from outside the plasma industry who are providing vital support to encourage more people to donate plasma.

"In addition to those announced at its inception - Biotest, BPL, CSL Behring, LFB, Octapharma and Takeda - the Alliance welcomes new industry members ADMA Biologics, BioPharma Plasma, GC Pharma, and Sanquin. Together, these organizations will contribute specialist advisory expertise, technical guidance and/or in-kind support to contribute to the Alliance goal of accelerating development and distribution of a potential treatment option for COVID-19."

*******

Here's an NPR story: Market For Blood Plasma From COVID-19 Survivors Heats Up
May 11, 2020

"In Minnesota, a program coordinated by the Mayo Clinic has collected plasma from more than 12,000 COVID survivors for transfusion into more than 7,000 gravely ill patients, the result of a massive public appeal led by government leaders and nonprofit groups such as the Red Cross.

"Meanwhile, for-profit companies that typically pay $50 per donation of plasma used in other lifesaving therapies are advertising aggressively — and significantly bumping up their rates for COVID donors.

"In Utah, John and Melanie Haering, who contracted COVID-19 aboard the ill-fated Diamond Princess cruise ship, received gift cards worth $800 after making two donations apiece at a Takeda Pharmaceuticals' BioLife Plasma Services center. BioLife runs several of the more than 800 paid-plasma collection sites in the U.S., part of an industry that produces plasma protein therapies used to treat rare, chronic conditions such as hemophilia and in medical emergencies."

Plasma and plasma products (such as antibodies) are a big business (and the U.S. dominates the international market)

These days I'm thinking about corona virus covid-19 convalescent blood plasma, which I blogged about yesterday, and about which I hope to say more soon. But that has gotten me to think again about blood plasma generally, which is a source of many therapies, including antibodies, immunoglobulins, that defend against a large variety of diseases.

The U.S. is the Saudi Arabia of blood plasma and plasma products, with both a large domestic commercial market and annual exports valued in the billions of dollars. The reason is largely that it is legal in the U.S. to pay plasma donors, so there's ample supply through a big network of hundreds of  for-profit and nonprofit blood and plasma centers (the nonprofits mostly don't pay donors, I think). In many countries, paying their residents for plasma is repugnant and illegal. Fortunately for their citizens, they mostly don't also suffer from severe shortages of life-saving plasma medicines, because it can be bought from the U.S. (See e.g. my posts on Canada's plasma policies.)

Here are some relevant export figures. They make clear that the U.S. exports billions of dollars of plasma, and tens of billions of dollars of plasma products.

For those who would like to study these data, let me explain where they come from.  (They  include some things that aren't plasma products, and may miss some that are...) It's not so easy to find the U.S exports of exactly blood plasma and plasma products (I needed some help).

In Chapter 30 of the U.S. International Trade Commission (USITC) Harmonized Tariff Schedule (HTS),is the code:
HTS 3002: "Human blood; animal blood prepared for therapeutic, prophylactic or diagnostic uses; antisera, other blood fractions and immunological products, whether or not modified or obtained by means of biotechnological processes; vaccines, toxins, cultures of micro-organisms (excluding yeasts) and similar products:
 Antisera, other blood fractions and immunological products, whether or not modified or obtained by means of biotechnological processes"

That sounds good, but it includes (aside from plasma products) things that I don't want to include e.g. Malaria diagnostic test kits, and Fetal Bovine Serum.

On the other hand the subcategory 3002.12.00  is for "Antisera and other blood fractions" which includes sub-subcategories for things I do want to include:
3002.12.10 Human blood plasma.
3002.12.20 Normal human blood sera, whether or not freeze-dried
3002.12.30 Human immune blood sera

And then there are are codes 3002.13.00, 14.00, and 15.00 which cover the promising (very similar) categories in which most of the immunoglobulins are probably found, but maybe some other things too:

Immunological products, unmixed, not put up in measured doses or in forms or packings for retail sale
Immunological products, mixed, not put up in measured doses or in forms or packings for retail sale
and
 Immunological products, put up in measured doses or in forms or packings for retail sale.

The place to go to turn these numbers into export figures is dataweb.usitc.gov  (But getting data there isn't completely straightforward, and I got help from Julia Fabens.)  The table above shows that whole plasma itself has over $2 billion of annual exports from the U.S., and together with plasma products, including those involving antibodies (immunological products) there are almost $20 billion of exports from the U.S.

So, I'm guessing that soon, if clinical trials show that antibodies against covid-19, are useful, they will become readily available, commercially, in plasma and in pharmaceuticals.  A year ago, those human antibodies didn't exist, and so there was no way to use it to help patient zero or the next many thousands.  But now there's a lot of it, more each day, in the blood of recovered patients.  And there's a whole industry devoted to collecting it and purifying the antibodies into "immunological products." 

I hope human antibodies against covid-19 are clinically useful, to help mitigate and cure the disease if not to prevent it, because my sense is that a vaccine is (at least) many months away.

102,597,746 2,627,504 1,586,634	102,597,746	2,627,504	1,586,634

Cascades of convalescent plasma for Covid-19, and chains of exchanges, by Kominers, Pathak, Sönmez, and Ünver

Covid-19 convalescent plasma is a new thing in the world, that came into existence only when the first human was infected and recovered from the Covid-19 disease that is now pandemic. It isn't clear yet whether it will be clinically valuable, but recovered antibodies have been valuable for some other diseases, so there's excellent reason to hope that will be the case now too.  And as the number of people grows who have recovered from Covid-19, it is likely that the supply of antibodies is growing much faster, since antibody-containing plasma can be donated once a month or so. (There are  ongoing studies of antibody production by recovered patients, examining how long the antibodies remain at high levels, post-recovery). Of course, most of that supply is sequestered in the blood of recovered patients, so there's a non-trivial issue of collection and distribution.

As readers of this blog know, many countries prohibit the sale of plasma. Will Americans continue to support a commercial market for Covid-19 convalescent plasma in the current pandemic?  A distinguished group of market designers has written a paper considering how to apply techniques developed for kidney exchange to the task of collecting convalescent plasma from recovered Covid-19 patients, if it becomes impossible to buy and sell it. In particular, they consider how to create chains of donations, without using money, to overcome the shortages they anticipate.

Here's an easy to read account by Scott Kominers, one of the authors.

How to End the Plasma Shortage for Coranavirus Patients

Scott Duke Kominers, Bloomberg News  May 11, 2020

"convalescent plasma is in short supply: although it’s hard to estimate precisely, some statistics suggest the U.S. may need twice as much as we have on hand.

"In a new paper, Parag A. Pathak, Tayfun Sonmez, M. Utku Unver and I propose a market design strategy that could help close the gap. Our approach makes use of two special features of the way plasma donation works.

"First, convalescent plasma is collected from recently recovered patients, which means that today’s patients become tomorrow’s prospective donors, assuming they manage to beat the virus. ... That suggests the shortage isn’t from lack of potential supply.

"Second, plasma donation is more than one-for-one: the typical donor can give enough plasma at one time for multiple treatments, and they can potentially donate more than once. As a result, assuming plasma therapy does help patients recover, there is a so-called flywheel effect: the more we use the treatment, the more plasma is available -- provided enough recovered patients are willing to donate.

"Many people would like to donate plasma to help a loved one, but can’t for various reasons:  Their blood types might be incompatible or they might live far away and be unable to travel. To address these sorts of obstacles, my collaborators and I suggest that each plasma donor could receive a voucher that can be used to give a family member or friend priority for plasma treatment. Because donation is more than one-for-one, it’s possible to honor vouchers while still increasing the pool of plasma available to treat other patients.

...

"A similar analysis suggests a role for a pay-it-forward system, where we make a point of treating patients who pledge to donate plasma, assuming they recover and are medically able to do so. Because recovered patients can typically donate more plasma than was needed for their own treatment, this again can help increase the plasma supply in the long run. As a result, my collaborators and I show that, somewhat paradoxically, prioritizing patients who pledge to donate can still end up expanding treatment for the patients who are unable to pledge, or just choose not to.

"Both of these policies are similar to systems we’ve used to expand kidney donation in the U.S.: Priority vouchers are sometimes granted when a living donor gives a kidney to a third-party before one of their family members needs a transplant. And pay-it-forward incentives are used in kidney exchange chains, where a patient with a medically incompatible prospective donor receives a kidney from a third-party donor, and then their donor later gives a kidney to some other patient."
******
Here is the paper itself:

Paying It Backward and Forward: Expanding Access to Convalescent Plasma Therapy Through Market Design
Scott Duke Kominers, Parag A. Pathak, Tayfun Sönmez, M. Utku Ünver
NBER Working Paper No. 27143
Issued in May 2020

Abstract: COVID-19 convalescent plasma (CCP) therapy is currently a leading treatment for COVID19. At present, there is a shortage of CCP relative to demand. We develop and analyze a model of centralized CCP allocation that incorporates both donation and distribution. In order to increase CCP supply, we introduce a mechanism that utilizes two incentive schemes, respectively based on principles of “paying it backward” and “paying it forward.” Under the first scheme, CCP donors obtain treatment vouchers that can be transferred to patients of their choosing. Under the latter scheme, patients obtain priority for CCP therapy in exchange for a future pledge to donate CCP if possible. We show that in steady-state, both principles generally increase overall treatment rates for all patients—not just those who are voucher-prioritized or pledged to donate. Our results also hold under certain conditions if a fraction of CCP is reserved for patients who participate in clinical trials. Finally, we examine the implications of pooling blood types on the efficiency and equity of CCP distribution.

Here's some of the motivation for their model:

"There is an active debate in economics and philosophy on the appropriate role of market-based

mechanisms with compensation for human products used in medicine or medical research like kidneys, blood, blood products, sperm, breast milk, bone marrow, and other.11 Since, as far as we know, there is no current market where infected patients can buy CCP or where recovered patients can sell CCP, we do not consider this possibility as part of our model.

...

"Because CCP is a form of plasma, a natural question is whether a compensated market for CCP will develop. In our model, there is no option to pay to receive CCP or be paid for donating CCP, but a donor can designate the voucher in our model to particular patient in need. As a result, our model of CCP falls between the two extremes described above. We expect that in a crisis moment, there is unlikely to be an active compensated market for CCP (even though it may be impossible to fully prohibit resale of vouchers). If a price-based market does develop, society may deem it unacceptable."

***************

I am more optimistic than they are about the likely available supply of convalescent plasma if it proves useful, through existing commercial channels. My optimism is based on the large thriving commercial market for plasma and plasma-derived antibodies in the U.S., and around the world.  I'll try to blog about the general plasma and antibody (immunoglobulin) market tomorrow, and perhaps more on Covid-19 antibodies later this week.

Buying and selling blood plasma, with focus on Canada, continued

Peter Jaworski writes:

"I had a video with Big Think come out recently where I defend paying for plasma against a number of objections. It’s a bit on the long side (17 minutes), but I thought you might be interested in posting it to your blog: https://bigthink.com/videos/paid-plasma-ethics

"I also had an opinion piece on the same topic published in the National Post (with Kate Vander Meer, who is a patient that used plasma therapies): https://nationalpost.com/opinion/opinion-on-covid-19-canada-needs-to-pay-plasma-donors-to-protect-its-domestic-supply?video_autoplay=true"

From the video transcript:

"Out of all the countries in the world only the ones that pay people to make that donation are self-sufficient in plasma therapies. And even the ones that pay not all of them are, in fact, sufficient. So there are only seven countries in the world that legally permit paying people for plasma donations – Germany, Austria, Hungary, Czechia or the Czech Republic, parts of Canada. And I'll talk about Canada in a second. The United States, of course, and China. Those are the seven countries in the world that permit payment. Every other country that does not allow payment for plasma donations imports plasma therapies that make use of plasma primarily from Americans. Germans as well, but primarily Americans. "
***********
And here's the op-ed:

Opinion on COVID-19: Canada needs to pay plasma donors to protect its domestic supply
Kate Vander Meer and Peter Jaworski: In order to ensure that enough people are willing to give plasma to meet the ever-expanding need, we must urgently adopt a pay-for-plasma model here at home

"There’s no evidence that anything other than paying for plasma will work. According to an expert panel formed by Health Canada in 2018, paid donors in countries that permit payment are responsible for providing 89 per cent of the plasma used to make therapies, with the United States alone providing 70 per cent of the global supply. The panel also revealed that no country in the world that forbids paid donations collects enough plasma to meet its needs — not one!"

Plasma donation, "convalescent plasma" and Covid-19 antibodies

Blood plasma is a big source of antibodies for people who don't make their own, and in these days of Covid-19 pandemic, antibodies are again in the news. As the number of recovering patients grows, can the antibodies they produce be of help in stemming the spread of the disease, or in curbing its intensity?

Here's a just published report of a quite preliminary study from China, in the PNAS:

Effectiveness of convalescent plasma therapy in severe COVID-19 patients
by Kai Duan, ... Xiaoming Yang (46 authors)
PNAS first published April 6, 2020 https://doi.org/10.1073/pnas.2004168117
Contributed by Zhu Chen, March 18, 2020 (sent for review March 5, 2020; reviewed by W. Ian Lipkin and Fusheng Wang)


"Significance: COVID-19 is currently a big threat to global health. However, no specific antiviral agents are available for its treatment. In this work, we explore the feasibility of convalescent plasma (CP) transfusion to rescue severe patients. The results from 10 severe adult cases showed that one dose (200 mL) of CP was well tolerated and could significantly increase or maintain the neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3 d. Radiological examination showed varying degrees of absorption of lung lesions within 7 d. These results indicate that CP can serve as a promising rescue option for severe COVID-19, while the randomized trial is warranted."
**********

Here's a story from the WSJ:

Coronavirus Survivors Keep Up the Fight, Donate Blood Plasma to Others
National Covid-19 project seeks volunteers to aid the seriously ill; ‘I feel obligated to help’
By Amy Dockser Marcus

"The Mount Sinai Hospital in New York, where Mr. Sherman volunteered to donate plasma, is one of 34 institutions around the country participating in the National Covid-19 Convalescent Plasma Project, which is seeking blood-plasma donations from recovered patients who have a confirmed Covid-positive test and are at least 21 days out from the onset of symptoms.
...
“The biggest problem is not the lack of donors,” said Arturo Casadevall, a professor at the Johns Hopkins Bloomberg School of Public Health, in Baltimore, and one of the organizers of the national project. “It is the logistics of figuring out how people who want to participate can actually donate.”

*********************

And here's a plasma industry press release:

Global Plasma Leaders Collaborate to Accelerate Development of Potential COVID-19 Hyperimmune Therapy

"Osaka, JAPAN, and King of Prussia, PA, USA – April 6, 2020 –  Biotest, BPL, LFB, and Octapharma have joined an alliance formed by CSL Behring (ASX:CSL/USOTC:CSLLY) and Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) to develop a potential plasma-derived therapy for treating COVID-19. The alliance will begin immediately with the investigational development of one, unbranded anti-SARS-CoV-2 polyclonal hyperimmune immunoglobulin medicine with the potential to treat individuals with serious complications from COVID-19.
...
"Developing a hyperimmune will require plasma donation from many individuals who have fully recovered from COVID-19, and whose blood contains antibodies that can fight the novel coronavirus. Once collected, the “convalescent” plasma would then be transported to manufacturing facilities where it undergoes proprietary processing, including effective virus inactivation and removal processes, and then is purified into the product."

********
My other posts on plasma, mostly focused on repugnance to compensation for donors. Here's one that explains some of the underlying medical issues:

Thursday, July 11, 2019

Plasma shortage alert from the IDF--the Immune Deficiency Foundation

Poll: majority of Canadians approve of paying plasma donors

New survey results from Peter Jaworski
Canadians think that pay-for-plasma is “morally appropriate.”

"A significant majority of Canadians (63%) believed that paying Canadians for plasma donations was “morally appropriate.”

By age, 18-34 year-olds were most likely to think that pay-for-plasma was “morally appropriate,” with 75% saying so. 70% of 35-54 year-olds, and 49% of those 55 or older thought pay-for-plasma was morally appropriate.

By region, 64% of Atlantic Canada, 69% in Quebec, 61% in Ontario, 70% in the Prairies, 65% in Alberta, and 56% in British Columbia held that opinion.

The provinces of Ontario (2014), Alberta (2017), and British Columbia (2018) have all recently banned pay-for-plasma citing moral objections as part of the motivation behind the prohibitions"

Peter Jaworski on paid and unpaid plasma donation in Canada

Peter Jaworski in the Globe and Mail:
There’s a way to avoid blood plasma shortages: pay donors

and on the radio in Calgary (it isn't Peter in the picture:)


Some quotes from the Globe and Mail article:
" Canada collects only about 17 per cent of the plasma necessary to meet domestic demand for immune globulin. Paid donors in the United States are how we meet (and exceed) our country’s demand."

"Only countries that pay donors are self-sufficient in plasma. The rest have to import it from countries that pay. Paid donors in the United States are responsible for more than 60 per cent of the entire world’s plasma used to make plasma medicine."

"In terms of safety, a Health Canada Expert Panel report from May of last year noted that paid plasma is not less safe than unpaid plasma and it is less expensive than trying to recruit and retain unpaid donors. Paying donors is also the most likely way of ensuring security of supply. Paid donations having a negative effect on unpaid blood donations is also unlikely. The United States has more than 800 paid plasma centres, and still has higher blood donation rates than Canada."

"Claims that paid plasma exploits the poor are also mistaken. Pay is about $30 an hour in Canada (it takes 1.5 hours to donate plasma), and represents about 30 per cent of the total revenue from a litre of plasma (a much larger share than profits, which are less than 3 per cent of revenue). That’s a fair deal."

"Opponents also like to point out that plasma collected in the paid plasma centres in Canada is exported, with none of it staying in Canada. That’s true, but it’s true because Canadian Blood Services choose not to buy Canadian plasma in spite of its lower price and domestic origins."

Plasma shortage alert from the IDF--the Immune Deficiency Foundation

Patients with primary immunodeficiencies don't produce antibodies, and depend on immunoglobulin, one of the primary plasma products produced by donated plasma (the other is albumin, and there are other life-saving and life-improving pharmaceuticals as well).  The IDF is a foundation dedicated to this complex of diseases:

Immune Deficiency Foundation
Dedicated to improving the diagnosis, treatment and quality of life of persons with primary immunodeficiencies

In recent years immunoglobulin has been used around the world to treat other immune deficiency diseases also, as well as to modulate the immune systems of people with auto-immune diseases.

But shortages occur, because the U.S. remains the primary supplier of donated plasma (since it is legal to compensate plasma donors in the U.S., but not everywhere...)

Here's a blog post from John Boyle, the IDF president

Immunoglobulin Product Availability Issues: The Sky Is Not Falling but the World Needs More Plasma
"IDF is working with those who are seeking to increase yields of Ig from plasma, introduce new fractionation technologies, grow plasma donations at collection centers, and more, but those are long term solutions.

"Ultimately, the issue is that the world needs more plasma, and the only good way to make that happen is to collect more plasma. The one thing that we can all do right now is to encourage people to become regular plasma donors if there’s a collection center anywhere near them."
***********

"Biologic" medicines are regulated by the Food and Drug Administration's
Center for Biologics Evaluation and Research (CBER)

"CBER is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products."

Here is their list of CBER-Regulated Products: Current Shortages
"GAMMAGARD LIQUID® Immune Globulin Infusion (Human) is currently available, though patient shipping schedules may be impacted as continued high demand exceeds production plans and available inventory."
which they attribute to: "Demand increase in the drug or biological product."