Ethical Payment in Human Infection Challenge Studies in the American Journal of Bioethics

 There are likely more vaccine trials ahead of us, of new vaccines and modifications of old ones to defend against new variants of covid. Here's a just-published paper, written when vaccine trials were still in the future. It's still relevant, because challenge trials (in which volunteers are exposed to a particular virus) can be much more focused than ordinary vaccine trials (particularly as the prevalence of disease begins to decline...see yesterday's post).

Promoting Ethical Payment in Human Infection Challenge Studies

Holly Fernandez Lynch, Thomas C. Darton, Jae Levy, Frank McCormick, Ubaka Ogbogu, Ruth O. Payne, Alvin E. Roth, Akilah Jefferson Shah, Thomas Smiley and Emily A. Largent            

Published online: 04 Feb 2021, The American Journal of Bioethics,  https://doi.org/10.1080/15265161.2020.1854368

Abstract: To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement. Within the basic framework, several factors are especially salient for HICS, and for SARS-CoV-2 HICS in particular, including the nature of participant confinement, anticipated discomfort, risks and uncertainty, participant motivations, and trust. These factors are reflected in a payment worksheet created to help sponsors, researchers, and ethics reviewers systematically develop and assess ethically justifiable payment amounts.

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Here's a link to the original (long) working paper:

Wednesday, August 19, 2020

The ethics (and some economics) of paying participants in Human Infection Challenge Studies, for a coronavirus vaccine

Multiple queues for Covid vaccines, as pharmacies join the supply chain

 It is good news that pharmacies are now being included among the places that can dispense Covid vaccinations, because not everyone is connected to another kind of health care provider.  But it will not end the congestion in getting appointments and delivering vaccines.

Having multiple waiting lists for appointments--i.e. for appointments at different pharmacy chains, health care providers, county vaccination centers--will add to congestion. People will have incentives to make appointments with more than one provider, because supplies at each provider are uncertain, so that some appointments may be cancelled due to shortages of vaccine on the appointed date.  After getting vaccinated, at least some people will neglect to cancel their other appointments, and so some doses of vaccine will not be delivered when scheduled. (Hopefully they won't be wasted).  So vaccinations will still be slower than we might hope.

Here's a CBS report:

Pharmacies now offering COVID-19 vaccines: Here's what you need to know BY KATE GIBSON

"The federal government this week started sending supplies of COVID-19 vaccines to 21 national drugstore chains and to independent pharmacies in a move to accelerate distribution. The program will be implemented in stages, based on available vaccine supplies, according to the U.S. Centers for Disease Control and Prevention.

...

"National drugstore chains CVS Health and Walgreens are among those getting supplies of COVID-19 vaccines from the federal government. But getting a shot isn't as easy as walking through the pharmacy door. Consumers are instead being discouraged from flocking to the stores, but rather get in line by making an appointment online or the phone. "

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Here's the CDC site:

Pharmacies Participating in the Federal Retail Pharmacy Program

Vaccination (and mask wearing) as repugnant transactions

 If a repugnant transaction is one that some people want to participate in, and other people think they shouldn't be allowed to (even those others aren't harmed by the participation of those who want to), then both vaccination and mask wearing are repugnant transactions, as Trumpism continues to work its way through the body politic.

Here's a story from the LA Times:

Dodger Stadium’s COVID-19 vaccination site temporarily shut down after protesters gather at entrance By MARISA GERBER, IRFAN KHAN

"Dodger Stadium’s mass COVID-19 vaccination site was temporarily shut down Saturday afternoon when about 50 protesters gathered at the entrance, frustrating hundreds of motorists who had been waiting in line for hours.

...

"The demonstrators included members of anti-vaccine and far-right groups. While some carried signs decrying the COVID-19 vaccine and shouting for people not to get the shots, there were no incidents of violence.

...

"A post on social media described the demonstration as the “Scamdemic Protest/March.” It advised participants to “please refrain from wearing Trump/MAGA attire as we want our statement to resonate with the sheeple. No flags but informational signs only.

“This is a sharing information protest and march against everything COVID, Vaccine, PCR Tests, Lockdowns, Masks, Fauci, Gates, Newsom, China, digital tracking, etc.”

...

"Protesters carried signs that read “Save Your Soul TURN BACK NOW,” “CNN IS LYING TO YOU,” “RECALL GAVIN NEWSOM” and “TAKE OFF YOUR MASK.”

...

“Unbelievable,” Los Angeles City Council President Nury Martinez tweeted. “If you don’t want the vaccine fine, but there are millions of Angelenos that do. 16,000 of your neighbors have died, so get out of the way.”

Paying employees to be vaccinated against Covid. (Is that repugnant? Could it be illegal??)

 Apparently paying workers to get vaccinated (even giving them paid time off to get vaccinated) may face some legal complications.

The Washington Post has the story:

Why grocery chains are paying workers to get vaccinated, but other industries are lagging   by By Jena McGregor and Taylor Telford

"A number of leading grocery chains are offering small cash bonuses and other incentives to encourage employees to get the coronavirus vaccine, in an effort that experts say could help speed protection of some of the country’s most vulnerable workers: low-paid, hourly retail workers.

"Dollar General, Trader Joe’s, Aldi and Lidl, as well as Instacart, have announced plans to promote the vaccine among employees, including flexible work schedules, paid time off to visit a vaccination site and bonuses of up to $200.

"The restaurant industry may also be moving toward incentives. On Tuesday, Darden Restaurants, which employs more than 175,000 workers across Olive Garden, LongHorn Steakhouse and many more brands, said it would offer up to four hours of paid time off to get the vaccine.

"However, few other companies have followed suit, potentially in part because of legal uncertainties involved with health screening questionnaires leading up to vaccination.

...

"Some lawyers believe companies will be able to successfully argue that the required screening questions for the coronavirus vaccine meet the standard of being needed for the business. 

...

"But others say the screening questions could complicate things if they’re seen as being part of a “voluntary wellness program,” which may limit the incentives companies can offer. If the employer contracts with an outside firm to vaccinate employees or has its own staff inoculate workers, new proposed rules from the U.S. Equal Employment Opportunity Commission, which says incentives can only be “de minimus” in size, might apply. The proposed rules give examples like a water bottle or gift card of “modest value.”

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Update: here's a related story from the Financial Times, focusing on the fact that there may be a shortage of vaccinated employees for some time:

Should Covid vaccines be mandatory at work? A few companies have introduced ‘no jab, no job’ policies, but it is unclear if such steps are lawful by Pilita Clark and Emma Jacobs

Vaccine delivery in the U.S. continues to be congested

As of today, congestion is still competing with short supply to limit vaccination in the US.

Some doses are being wasted or delayed in the name of fairness,  to better honor the priority orderings being used in each state, some doses are being sequestered for second vaccinations rather than being used now for first vaccinations, and some regions and/or providers have too little vaccine on hand, or too little predictability of supply to plan efficient distribution.

 USA today has the story:

Amid sputtering COVID-19 vaccine rollout, 16 states have used less than half of distributed doses  by Ken Alltucker

"The Biden administration has vowed drug companies will make enough vaccine to immunize 300 million Americans by the end of the summer.

But getting the vaccine from the factory to the arms of people has been anything but smooth. Of 47.2 million doses shipped to states and nursing homes, 24.6 million doses have been administered, the Centers for Disease Control and Prevention reported Thursday. 

The nation's slow rollout has boiled over from California, which tapped Blue Shield of California to allocate vaccines, to Maryland where Gov. Larry Hogan implored the federal government to send more doses of the potentially life-saving vaccine.

An Arlington, Virginia, hospital canceled 10,000 vaccine appointments, citing the state's decision to send doses to county health departments rather than directly to hospitals and other health providers.  In Minnesota, a vaccine lottery offered just 8,000 appointments to more than 226,000 people who signed up over a 24-hour period this week."

Congestion in vaccine delivery, and shortage of overall supply: latest news, and a call for increased production

Covid vaccines in many parts of the U.S. are being distributed only slowly, while other places are experiencing shortages.

 The NY Times brings us up to date:

New Pandemic Plight: Hospitals Are Running Out of Vaccines.  Health officials are frustrated that available doses are going unused while the virus is killing thousands of people each day. Many vaccine appointments have been canceled.   By Simon Romero and Giulia McDonnell Nieto del Rio

"In the midst of one of the deadliest phases of the pandemic in the United States, health officials in Texas and around the country are growing desperate, unable to get clear answers as to why the long-anticipated vaccines are suddenly in short supply. Inoculation sites are canceling thousands of appointments in one state after another as the nation’s vaccines roll out through a bewildering patchwork of distribution networks, with local officials uncertain about what supplies they will have in hand.

...

"Health officials trying to piece together why this is happening are puzzled by reports that millions of available doses are going unused. As of Friday morning, nearly 39.9 million doses of the Pfizer-BioNTech and Moderna vaccines had been distributed to state and local governments, but only about 19.1 million doses had been administered to patients, according to the Centers for Disease Control and Prevention....

...

"“Right now, in many cities and counties when an announcement of available vaccinations is made, website sign-up pages crash and phone calls go unanswered"

...

"The public health department in San Francisco and hospitals in the city were “caught by surprise” by the lack of doses, Dr. Rutherford said, and by the eligibility expansion to those 65 and older, which likely strained the system. Varying vaccine distribution channels — such as Kaiser Permanente and the University of California, San Francisco — receive the doses on their own, he said, further complicating an already convoluted distribution system.

“So it’s a little hard for the city to understand exactly what’s left over, what they need to do, where the holes are to fill,” Dr. Rutherford said. Still, new vaccination sites are opening in San Francisco, which Dr. Rutherford said would help speed the process along once more doses become available. “There’s this tension between efficiency and equity,” he said. “It’s never easy.”

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Here's a paper that points out that getting people vaccinated fast would have enormous benefits in terms of saving lives and reopening the economy, and that once we get the kinks out of vaccine distribution, it makes sense to invest in production facilities much faster than the pharma companies might feel it was necessary to do on their own.

Preparing for a Pandemic: Accelerating Vaccine Availability  By AMRITA AHUJA, SUSAN ATHEY, ARTHUR BAKER, ERIC BUDISH, JUAN CAMILO CASTILLO, RACHEL GLENNERSTER, SCOTT DUKE KOMINERS, MICHAEL KREMER, JEAN LEE, CANICE PRENDERGAST, CHRISTOPHER M. SNYDER, ALEX TABARROK, BRANDON JOEL TAN, WITOLD WIECEK

Abstract: Vaccinating the world’s population quickly in a pandemic has enormous health and economic benefits. We analyze the problem faced by governments in determining the scale and structure of procurement for vaccines. We analyze alternative approaches to procurement, arguing that buyers should directly fund manufacturing capacity and shoulder most of the risk of failure, while maintaining some direct incentives for speed. We analyzed the optimal portfolio of vaccine investments for countries with different characteristics as well as the implications for international cooperation. Our analysis, considered in light of the experience of 2020, suggests lessons for future pandemics.

Vaccine congestion: short planning horizons

 ProPublica has the story:

How Operation Warp Speed Created Vaccination Chaos--States are struggling to plan their vaccination programs with just one week’s notice for how many doses they’ll receive from the federal government. The incoming Biden administration is deciding what to do with this dysfunctional system.       by Caroline Chen, Isaac Arnsdorf and Ryan Gabrielson

"Hospitals and clinics across the country are canceling vaccine appointments because the Trump administration tells states how many doses they’ll receive only one week at a time, making it all but impossible to plan a comprehensive vaccination campaign.

"The decision to go week by week was made by Operation Warp Speed’s chief operating officer, Gen. Gustave Perna, because he didn’t want to count on supplies before they were ready. Overly optimistic production forecasts turned out to be a major disappointment in the rollout of the H1N1 vaccine more than a decade ago, also leading to canceled appointments and widespread frustrations with the government’s messaging.

"This time, however, the most pressing problem isn’t the overpromising of supply. For each of the past three weeks, the federal government got about 4.3 million shots. But the amount that each state is sent has fluctuated as Operation Warp Speed changes the quantities available week by week.

State health officials say the unpredictable shipments have led to chaos on the ground, including the inability to quickly use up all of the doses sent to them. The week-by-week system also makes it hard to plan for the second doses that everyone needs because they come three or four weeks after the initial dose.

...

"The makers of the two authorized vaccines, Pfizer and Moderna, are each contracted to supply 100 million doses by the end of March. But with just 31.2 million delivered as of Jan. 15, according to data from the Centers for Disease Control and Prevention, the companies will need to ramp up their pace to hit their targets."

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HT: Peter Cramton

Covid vaccine causes outbreak of smoking in New Jersey

 Strategy-proofness is an idea that shouldn't be appreciated only by game theorists.

The NY Times has the story:

Smokers in N.J. Are Eligible for Vaccine. No Proof Needed. New Jersey is one of only two states that has included smoking among the high-risk medical conditions that make people eligible for the Covid-19 vaccine.

More on convalescent plasma for treating Covid-19

Early results concerning the effectiveness of convalescent plasma have been mixed.  Here's a new study, in the NEJM, and reported in the NY Times. (see my earlier posts here.)

Here's the Times story:

Blood Plasma Reduces Risk of Severe Covid-19 if Given Early  By Katherine J. Wu

"A small but rigorous clinical trial in Argentina has found that blood plasma from recovered Covid-19 patients can keep older adults from getting seriously sick with the coronavirus — if they get the therapy within days of the onset of the illness.

"The results, published Wednesday in the New England Journal of Medicine, are some of the first to conclusively point toward the oft-discussed treatment’s beneficial effects."

And here's the NEJM article:

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

List of authors.

Romina Libster, M.D., Gonzalo Pérez Marc, M.D., Diego Wappner, M.D., Silvina Coviello, M.S., Alejandra Bianchi, Virginia Braem, Ignacio Esteban, M.D., Mauricio T. Caballero, M.D., Cristian Wood, M.D., Mabel Berrueta, M.D., Aníbal Rondan, M.D., Gabriela Lescano, M.D., et al., for the Fundación INFANT–COVID-19 Group*

"BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. "

Vaccine supply chain woes

Supply chains are boring, until things are in short supply. And there are many steps in a supply chain that can cause supplies to be short. Below are some news stories on how the U.S. is having trouble delivering vaccines, with the limiting factors not yet being shortage of the vaccines themselves.

I notice a few things about these stories. 

• It seems to be widely recognized that it is worth spending billions (or at least hundreds of millions) to save trillions (i.e. to speed up vaccinations to hasten the reopening of the economy).
• It seems also to be widely recognized that it would be regarded as repugnant to allocate initial inoculations by charging high prices for them while they are scarce: instead we are trying to establish priority orders for recipients: e.g. first health care workers and the elderly in nursing homes, then the independent elderly and the ill, etc,
• Keeping strictly to priorities may partly be what is slowing down vaccinations: when not enough high priority people show up, the vaccines go back in the freezer to wait for the next day (at least I hope they go back in the freezer, and are not spoiled and unusable by the next day).  It might be better to try to find people ready to be vaccinated, when it's hard to find enough high priority people quickly.
• A lack of confidence that more vaccine doses will be reliably arriving on schedule is causing some stockpiling, which is the enemy of fast distribution.
• Holiday schedules make it hard to get lots of people vaccinated fast; maybe we'll do better this coming week.

Here's a story from the Financial Times:

Trump administration admits missing Covid vaccination goals--Officials say US states have used only a fifth of the doses they were given  by Kiran Stacey 

"Officials had aimed to distribute enough doses to vaccinate 20m people by the end of the year, but recently admitted they were not likely to hit that target until early January after underestimating how long it would take to perform quality control checks on manufactured doses.

"Figures released by the federal government, however, show a bigger hurdle is getting the vaccines to people once they have been manufactured and sent out. The US Centers for Disease Control and Prevention said on Wednesday just under 2.6m people in the country had been vaccinated, even though 12.4m doses had been distributed.

...

"Nancy Messonnier, the director of the National Center for Immunisation and Respiratory Diseases, blamed a range of factors. She said part of the problem was that pharmacies that were largely responsible for vaccinating people in care homes had been waiting to schedule appointments until they could be sure they had enough doses to perform booster shots."

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From the NY Times:

Here’s Why Distribution of the Vaccine Is Taking Longer Than Expected--Health officials and hospitals are struggling with a lack of resources. Holiday staffing and saving doses for nursing homes are also contributing to delays.  By Rebecca Robbins, Frances Robles and Tim Arango

"In Florida, less than one-quarter of delivered coronavirus vaccines have been used, even as older people sat in lawn chairs all night waiting for their shots. In Puerto Rico, last week’s vaccine shipments did not arrive until the workers who would have administered them had left for the Christmas holiday. In California, doctors are worried about whether there will be enough hospital staff members to both administer vaccines and tend to the swelling number of Covid-19 patients.

"These sorts of logistical problems in clinics across the country have put the campaign to vaccinate the United States against Covid-19 far behind schedule in its third week, raising fears about how quickly the country will be able to tame the epidemic.

...

"Complicating matters, the county health department gets just a few days of notice each week of the timing of its vaccine shipments. When the latest batch arrived, Dr. Gayles’s team scrambled to contact people eligible for the vaccine and to set up clinics to give out the doses as fast as possible.

...

"In Florida, some hospital workers offered the vaccine declined it, and those doses are now designated for  other vulnerable groups like health care workers in the community and the elderly, but that rollout has not quite begun

...

"It may be more difficult, public health officials say, to vaccinate the next wave of people, which will most likely include many more older Americans as well as younger people with health problems and frontline workers. Among the fresh challenges: How will these people be scheduled for their vaccination appointments? How will they provide documentation that they have a medical condition or a job that makes them eligible to get vaccinated? And how will pharmacies ensure that people show up, and that they can do so safely?"

A hopeful picture for 2021 (when vaccines will replace masks...)

 

Original at https://pbs.twimg.com/media/EqayYuaXEAE7YCu.jpg

HT: Mike Rees

Fast Covid vaccine development --science and funding

 Here's a news article from Nature:

The lightning-fast quest for COVID vaccines — and what it means for other diseases.

The speedy approach used to tackle SARS-CoV-2 could change the future of vaccine science. by Philip Ball

"The research that helped to develop vaccines against the new coronavirus didn’t start in January. For years, researchers had been paying attention to related coronaviruses, which cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), and some had been working on new kinds of vaccine — an effort that has now paid off spectacularly.

"Conventional vaccines contain viral proteins or disabled forms of the virus itself, which stimulate the body’s immune defences against infection by a live virus. But the first two COVID-19 vaccines for which efficacy was announced in large-scale (phase III) clinical trials used just a string of mRNA inside a lipid coat. The mRNA encodes a key protein of SARS-CoV-2; once the mRNA gets inside our cells, our bodies produce this protein. That acts as the antigen — the foreign molecule that triggers an immune response. The vaccines made by Pfizer and BioNTech and by the US pharmaceutical company Moderna both use mRNA that encodes the spike protein, which docks to human cell membranes and allows the coronavirus to invade the cell.

...

"The approach has matured just at the right time; five years ago, the RNA technology would not have been ready.

...

"The slowest part of vaccine development isn’t finding candidate treatments, but testing them. This often takes years (see ‘Vaccine innovation’), with companies running efficacy and safety tests on animals and then in humans. Human testing requires three phases that involve increasing numbers of people and proportionately escalating costs. The COVID-19 vaccines went through the same trials, but the billions poured into the process made it possible for companies to take financial risks by running some tests at the same time."

HT: Muthu Muthukrishnan

Allocating vaccines while they're still scarce--I'm interviewed by Stacy Vanek Smith on the Indicator from Planet Money

 Here's a podcast in which I'm interviewed by Stacey Vanek Smith about how vaccines might be allocated while still scarce:

Who Gets A Vaccine? A Conversation With Alvin Roth

The Indicator from Planet Money, December 15, 2020

("9-Minute Listen")

And here's the transcript.

Below is the latter part of the interview, about vaccines (edited by me to take out excess "you know's," you know?):

SMITH: What are - when you're looking at the vaccine situation now, there are a limited number of COVID vaccines available, at least at this moment. What do you see when you look at that market right now? Not that it's a market per se but you know what I mean.

ROTH: Any time we're allocating scarce resources,  I think it's fair to talk about that as the marketplace. It's waiting for a scarce resource to become available. So what we do with [deceased donor] organs is we form waiting lists and each organ has a different kind of waiting list. So that's a little bit like what we're going to see with a vaccine. Different states are going to have different rules of how to get vaccines. They also have different supply and demand. It might be that lots of people in New York will want to have a vaccine. And it's possible - and I'm purely speculating - that a smaller percentage of people in Tennessee will want it, right? We have a lot of vaccine hesitancy in the United States.

SMITH: Yeah.

ROTH: So one thing that reminds me of kidney exchange a little bit is exchange. Supposing it turns out that we allocate to the states proportional to population, which I think we may be doing this morning. And suppose it turns out that in New York, there's a giant shortage, that there are lots of health care workers, and they're eager to get it. And then after that, there are lots of old people and vulnerable people of various sorts. And New York will develop a priority list.

At the same time, they might discover that in Tennessee, they've gotten more vaccines than they can get rid of on the first day because of vaccine hesitancy or maybe people aren't eager to try it out so early. So you could imagine an exchange, that we'll send you 100,000 doses today and call them in two months when we think we'll need them.

SMITH: What would - like, what do you think is sort of an ideal way for states and I guess - and countries to start approaching this? Because it is complicated, and everybody wants this vaccine, right? A lot of people want this vaccine right now. The demand is greater than the supply. Like, what would you I guess like to see happen or like to see start happening for countries and states kind of making this decision?

ROTH: One thing that people have said is, health care workers are important because they help us contain the disease. But they're also vulnerable to it  - especially if we talk about the health care workers who are treating people who are ill with COVID. So it might make sense to prioritize them so that the hospitals don't shut down, things like that.

But then you might also say, people who are at risk in various ways should get a high priority because getting a vaccine might save their life. But then we might want to go in a different direction. We might want to say - who is likely to be a superspreader? Who  is exposed by the nature of their work? Maybe the essential workers who drive the trucks and deliver the goods and coming to your door and maybe getting your signature.

SMITH: Right, right 'cause this is a little different than a kidney because we're talking about a virus that can spread. So that's in there, too. Like, people who are more likely to - 'cause if we can vaccinate, let's say, like, people who do deliveries, then that could pay sort of exponential dividends.

ROTH: Right. And then we could also think about what's costly to us about the precautions we're taking. One of those things, of course, is child care. If you have school-age children and they're now at home and especially if they're quite young, so they can't even really do Zoom classes without your help, well, then someone in your household is not working very hard 'cause they're providing a service that teachers used to provide. So we might think about what set of vaccinations would be required to open up schools again 'cause that would be a big weight lifted off the economy.

SMITH: Oh, right. That would be - that would help in, like, other ways because then it could help people go back to work, yeah.

ROTH: You'd like there to be the biggest multiplier effect you can get for each vaccine that not only does good for the person getting the jab, you know, the needle in his upper arm but that jab should also do the most good for the most other people.

SMITH: Dr. Alvin Roth is a professor of economics at Stanford University and winner of the 2012 Nobel Prize in Economics.

This episode of THE INDICATOR was produced by Nick Fountain, fact-checked by Sean Saldana. THE INDICATOR is edited by Paddy Hirsch and is a production of NPR.

Copyright © 2020 NPR. All rights reserved. Visit our website terms of use and permissions pages at www.npr.org for further information.

NPR transcripts are created on a rush deadline by Verb8tm, Inc., an NPR contractor, and produced using a proprietary transcription process developed with NPR. This text may not be in its final form and may be updated or revised in the future. Accuracy and availability may vary. The authoritative record of NPR’s programming is the audio record.

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A quick note on interviews.  These 9 minutes came from a one hour interview, so lots of decisions about what to include were made by NPR. (That’s why I come off as a solitary hero in the initial discussion of kidney exchange.)  But, aside from that, the editors did a pretty good job on this one, imho...)

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

Pandemic inspired changes in the economy that may last--real estate and medicine

 In academia, Zoom seminars may coexist with in-person seminars long after the pandemic has ended. They aren't as nice as in-person seminars, but they involve much less air travel.

Business meetings too can more easily be conducted remotely these days, through Zoom, Google Meet, Microsoft Teams, etc. Once again, there's something missing compared to in person meetings, but that's counterbalanced by the skipped travel.

Exercise has changed--fewer visits to the gym, but internet companies like Peloton and Mirror combine home gym equipment with workouts in internet gym classes.

Here are some other items that have caught my eye:

Real Estate Transactions Go Virtual--The traditional real estate closings with a room full of people and stacks of documents are becoming a memory, as much of the process is now online.  By Sydney Franklin in the NY Times

"Real estate transactions have gone largely digital as the pandemic has disrupted nearly every aspect of home buying, from house hunting to securing a mortgage, getting an appraisal, notarizing documents and signing the final closing documents.

...

"While some clients continue to prefer in-person closings, others are giving their lawyers power of attorney to sign the final documents for them or they’re executing closings on virtual platforms like DocuSign.

...

"By the time New York’s real estate market reopened in June after several months of coronavirus restrictions, most buyers were prioritizing virtual tours before reaching out for an in-person visit.

...

"Since March 31, an executive order by Gov. Andrew M. Cuomo has allowed notaries in New York to sign documents using audio-video technology instead of signing and notarizing documents in person.

"Dawn Pereyo, an underwriter and past president of the New York State Land Title Association, says this work flow is the way of the future. Twenty-nine states, not including New York, have already enacted permanent remote online notarization (RON) legislation. “The executive order has allowed us to start down the road of RON,” she said.

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

And this:

20 Ways 2020 Changed How We Use Technology Forever--Our reliance on technology while isolated at home these past months—whether Zooming into weddings or FaceTiming with doctors—has permanently altered our relationship to gadgets.   By Matthew Kitchen in the WSJ

"telemedicine and teletherapy visits became the norm. According to a survey by the American Psychiatric Association, the percentage of patients regularly using some form of telehealth with a professional rose from 2.1% pre-pandemic to more than 84.7% as of this summer."

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-

Challenge trials for Covid-19 vaccine are being planned (and a recent NBER cost/benefit analysis)

 Here's the NY Times:

To Test Virus Vaccines, U.K. Study Will Intentionally Infect Volunteers--The hotly contested strategy of deliberate exposure, known as a human challenge trial, could speed up the process of identifying effective coronavirus vaccines.  By Benjamin Mueller

"Scientists at Imperial College London plan to deliberately infect volunteers with the coronavirus early next year, launching the world’s first effort to study how vaccinated people respond to being intentionally exposed to the virus and opening up a new, uncertain path to identifying an effective vaccine.

"The hotly contested strategy, known as a human challenge trial, could potentially shave crucial time in the race to winnow a number of vaccine candidates. Rather than conducting the sort of trials now underway around the world, in which scientists wait for vaccinated people to encounter the virus in their homes and communities, researchers would purposely infect them in a hospital isolation unit.

"Scientists have used this method for decades to test vaccines for typhoid, cholera and other diseases, even asking volunteers in the case of malaria to expose their arms to boxes full of mosquitoes to be bitten and infected. But whereas the infected could be cured of those diseases, Covid-19 has few widely used treatments and no known cure, putting the scientists in charge of Britain’s study in largely uncharted ethical territory.

...

"The volunteers in London will be paid roughly Britain’s minimum wage, which is about £9, or $11, per hour, for their time in taking part in the trial and their two to three weeks in mandatory quarantine. The researchers said they were wary of offering additional incentives that could cloud the judgment of volunteers."

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

And here's a recent NBER paper on the efficiency of challenge trials:

A Cost/Benefit Analysis of Clinical Trial Designs for COVID-19 Vaccine Candidates

Donald A. Berry, Scott Berry, Peter Hale, Leah Isakov, Andrew W. Lo, Kien Wei Siah & Chi Heem Wong

ID w27882, DOI 10.3386/w27882, October 2020

Abstract: We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional randomized clinical trials and adaptive and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 504 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits—averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design—if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.

Paying participants in challenge trials of Covid-19 vaccines, by Ambuehl, Ockenfels, and Roth

 Here's a new short paper in Journal of Medical Ethics: (it's ungated, you can read it all at the link): 

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-

"Participants in medical studies perform a service. Outside the domain of research participation, there is nearly universal agreement that workers providing a service should be compensated fairly, and that work involving more discomfort and risk should be compensated more generously. Accordingly, labour regulations impose floors (minimum wage laws), not caps on compensation. Caps, even if intended to protect against undue inducement, also raise concerns about illegal price-fixing that disadvantages workers. Such limits on payment for egg donors have successfully been challenged in court.

...

"Payment caps can lead to attempts to circumvent the regulation. For example, many countries that prevent payment for the donation of blood plasma instead import it from the USA where payment is legal—the volume of the US export market for plasma products approaches $20 billion per year.ii Similarly, restrictions on CHIM trial payments may lead to an increase in trials in countries with less stringent regulation.

...

"we note that increasing hourly pay by a risk-compensation percentage as proposed in the target article provides compensation proportional to risk only if the risk increases proportionally with the number of hours worked. (Some risky tasks take little time; imagine challenge trials to test bulletproof vests.) To ensure that equal consequences are compensated with equal amounts across a wide variety of studies, we instead recommend a three-part contract consisting of: (1) salary for time involvement that is adjusted to account for the amount of discomfort experienced during participation, (2) insurance against ex post adverse outcomes and (3) ex ante compensation for risks that cannot be compensated ex post (such as death). Such a scheme also increases transparency about what is requested from participants and thus contributes to high-quality participation decisions."

...

"The current discussion about payment in challenge trials is important because the potential benefits of well-designed challenge trials that could accelerate the development of safe and effective vaccines are enormous. Overall, economic research has shown, first, that ethical concerns over high payments may rely on intuitive predictions about behavioural effects that find little or no empirical support, and that the dangers of underpayment are at least as real as those of overpayment. Second, a part of the ethics literature attaches significantly more weight to concerns of undue inducement than the general population. Accordingly, it appears to us that there is sufficient public support for preparing for challenge trials, with paid participants, without a need for excessive ethical concern that payments might inadvertently become too generous to trial participants."

***********

Our article is an invited commentary on

• Payment in challenge studies: ethics, attitudes and a new payment for risk model

  Olivia Grimwade Julian Savulescu Alberto Giubilini Justin Oakley Joshua Osowicki Andrew J Pollard Anne-Marie Nussberger  J Med Ethics, 2020

Related comments appear in

1. Compensating for research risk: permissible but not obligatory
   Holly Fernandez Lynch et al., J Med Ethics
2. Payment of COVID-19 challenge trials: underpayment is a bigger worry than overpayment
   Jennifer Blumenthal-Barby et al., J Med Ethics, 2020
3. How much money would it take for you to be infected with COVID-19 for research?
   
   By Olivia Grimwade and Julian Savulescu., JME blog, 2020

Broad public support for challenge trials for Covid-19 vaccines

 A broad based survey suggests that challenge trials are not generally regarded as repugnant.

Broad Cross-National Public Support for AcceleratedCOVID-19 Vaccine Trial Designs

by David Broockman, Joshua Kallay, Alexander Guerrero, Mark Budolfson, Nir Eyal, Nicholas P. Jewell , Monica Magalhaes,  Jasjeet S. Sekhony

Abstract: A vaccine for COVID-19 is urgently needed. Several vaccine trial designs may significantly accelerate vaccine testing and approval, but also increase risks to human subjects. Concerns about whether the public would see such designs as ethically acceptable represent an important roadblock to their implementation, and the World Health Organization has called for consulting the public regarding them. Here we present results from a pre-registered cross-national survey (n = 5,920) of individuals in Australia, Canada, Hong Kong, New Zealand, South Africa, Singapore, the United Kingdom, and the United States. The survey asked respondents whether they would prefer scientists to conduct traditional trials or one of two accelerated designs: a challenge trial or a trial integrating a Phase II safety and immunogenicity trial into a larger Phase III efficacy trial. We find broad majorities prefer for scientists to conduct challenge trials (75%, 95% CI: 73-76%) and integrated trials (63%, 95% CI: 61-65%) over standard trials. Even as respondents acknowledged the risks, they perceived both accelerated trials as similarly ethical to standard trial designs, and large majorities characterized them as "probably" or "definitely ethical" (72%, 95% CI: 70-73% for challenge trials; 77%, 95% CI 75-78% for integrated trials). This high support is consistent across every geography and demographic subgroup we examined, including people of diverging political orientations and vulnerable populations such as the elderly, essential workers, and racial and ethnic minorities. These findings bolster the case for these accelerated designs and can help assuage concerns that they would undermine public trust in vaccines.

How King Uzziah became corrupt and was stricken with Covid and quarantined (II Chronicles 26)

Chronicles II chapter 26 describes how King Uzziah became corrupt and power hungry, so that the Lord infected him with the untranslatable disease that the Chronicler called "zaraath," which required him to be quarantined for the rest of his life.

Here it is, starting from verse 16.
 

And when he became strong, his heart became haughty until he became corrupt, and he trespassed against the Lord his God, and he came into the Temple of the Lord to burn incense on the altar of incense.		טזוּכְחֶזְקָת֗וֹ גָּבַ֚הּ לִבּוֹ֙ עַד־לְהַשְׁחִ֔ית וַיִּמְעַ֖ל בַּֽיהֹוָ֣ה אֱלֹהָ֑יו וַיָּבֹא֙ אֶל־הֵיכַ֣ל יְהֹוָ֔ה לְהַקְטִ֖יר עַל־מִזְבַּ֥ח הַקְּטֹֽרֶת:
17And Azariah the priest came after him, and ,with him were priests of the Lord, eighty mighty men.		יזוַיָּבֹ֥א אַֽחֲרָ֖יו עֲזַרְיָ֣הוּ הַכֹּהֵ֑ן וְעִמּ֞וֹ כֹּֽהֲנִ֧ים| לַֽיהֹוָ֛ה שְׁמוֹנִ֖ים בְּנֵי־חָֽיִל:
18And they stood beside Uzziah the king and said to him, "It is not for you, Uzziah, to burn incense to the Lord, but for the priests, sons of Aaron, who are consecrated to burn [incense]. Leave the Sanctuary, for you have trespassed, and it will not be glory for you from the Lord God."		יחוַיַּֽעַמְד֞וּ עַל־עֻזִּיָּ֣הוּ הַמֶּ֗לֶךְ וַיֹּ֚אמְרוּ לוֹ֙ לֹֽא־לְךָ֣ עֻזִּיָּ֗הוּ לְהַקְטִיר֙ לַֽיהֹוָ֔ה כִּ֣י לַכֹּֽהֲנִ֧ים בְּנֵי־אַֽהֲרֹ֛ן הַֽמְקֻדָּשִׁ֖ים לְהַקְטִ֑יר צֵ֚א מִן־הַמִּקְדָּשׁ֙ כִּ֣י מָעַ֔לְתָּ וְלֹֽא־לְךָ֥ לְכָב֖וֹד מֵֽיְהֹוָ֥ה אֱלֹהִֽים:
19And Uzziah became furious, and in his hand was a censer to burn, and in his fury with the priests, the zaraath shone upon his forehead before the priests in the House of the Lord, over the altar of incense.		יטוַיִּזְעַף֙ עֻזִּיָּ֔הוּ וּבְיָד֥וֹ מִקְטֶ֖רֶת לְהַקְטִ֑יר וּבְזַעְפּ֣וֹ עִם־הַכֹּֽהֲנִ֗ים וְ֠הַצָּרַעַת זָֽרְחָ֨ה בְמִצְח֜וֹ לִפְנֵ֚י הַכֹּֽהֲנִים֙ בְּבֵ֣ית יְהֹוָ֔ה מֵעַ֖ל לְמִזְבַּ֥ח הַקְּטֹֽרֶת:
20And Azariah, the chief priest, and all the priests, turned to him, and behold he was stricken with zaraath on his forehead; so they rushed him out of there, and he too hastened to leave, for the Lord had smitten him.		כוַיִּ֣פֶן אֵלָ֡יו עֲזַרְיָהוּ֩ כֹהֵ֨ן הָרֹ֜אשׁ וְכָל־הַכֹּֽהֲנִ֗ים וְהִנֵּה־ה֚וּא מְצֹרָע֙ בְּמִצְח֔וֹ וַיַּבְהִל֖וּהוּ מִשָּׁ֑ם וְגַם־הוּא֙ נִדְחַ֣ף לָצֵ֔את כִּ֥י נִגְּע֖וֹ יְהֹוָֽה:
21And King Uzziah was stricken with zaraath until the day of his death, and he lived in a house of retirement, for it had been decreed from the House of the Lord,

HT: Aviya Kushner in the Forward