Results for “challenge trials”
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Debate: The Ethics of Tuberculosis Challenge Trials

On Wed. Jan 12 there will be a live online debate on the bioethics question, If wild type tuberculosis challenge studies would be useful, would they be ethical to conduct? The debate will feature debaters from the The Rikers Debate Project:

  • Jerusalem Demsas, Policy Writer at Vox.com
  • Kaamilya Finley, Senior One Team Ambassador, Deloitte & Rikers Debate Project Fellow
  • Charles Hopkins, President, National Action Network – PG County, Maryland & Rikers Debate Project Fellow
  • Brian Patrick, Activist, Artist, & Rikers Debate Project Fellow

and will be judged by a panel of experts, policy makers and interested parties including myself:

  • Gabriel Bankman-Fried, Director, Guarding Against Pandemics
  • Camilla Broderick, Community Navigator for Midtown Community Court & Rikers Debate Project Fellow
  • Ann M. Ginsberg, Deputy Director, TB Vaccines Global Health
  • Phil Krause, Former Deputy Director, FDA/CBER/OVRR
  • Jake Liang, Chief of Liver Diseases Branch & Deputy Director of Translational Research, NIDDK, NIH
  • Larissa MacFarquhar, Staff Writer, The New Yorker
  • Matt Memoli, Director, Clinical Studies Unit, IRP’s Laboratory of Infectious Disease, NIAID
  • Jerry Sadoff, Head of Early Development, Crucell Vaccine Institute, Janssen Pharmaceutical Companies of Johnson & Johnson
  • Alex Tabarrok, Professor of Economics, George Mason University
  • Nikki Teran, Senior Biosecurity Fellow, The Institute for Progress
  • Matthew Yglesias, Founder, Slow Boring

Should be fun. Admission is free and you can register for attendance here.

The Strange Death of Human Challenge Trials

A good post at the Effective Altruism Forum on all the stuff we could have done to stop the pandemic but didn’t:

Probably the biggest mistake was not intentionally infecting vaccinated volunteers. This could be done in 1 month, vs 6.5 months for the ecological trials that the entire world did out of misguided PR ethics. (2.5 is probably more realistic given signups, approvals, and big pharma’s slow data analysis and reporting. That’s still hundreds of thousands of lives.)

1DaySooner wrote a letter. The world’s foremost consequentialist signed. The world’s foremost deontologist signed. Two of the most prominent bioethicists in the world signed. 15 Nobelists signed. Dozens of philosophers who otherwise agree on extremely little signed. But they’re unethical.

Rarely do I so strongly feel the boot of others on my neck, and humanity’s neck.

The one distinctively courageous thing about the UK – the human challenge trials which got 40,000 volunteers – actually eventually started!.. In January 2021, with n=90.

I am extremely puzzled why China or one of the other ahem non-individualist governments didn’t do these.

Lots more at the link.

The public is fine with Human Challenge Trials

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.

Here is the paper by David Broockman, et.al.

Challenge Trials in Britain!

From the FT:

London is to host the world’s first Covid-19 human challenge trials — in which healthy volunteers are deliberately infected with coronavirus to assess the effectiveness of experimental vaccines. The UK government-funded studies are expected to begin in January at a secure quarantine facility in east London, according to several people involved in the project, which will be announced next week.

…The project’s academic leader is Imperial College London, and it will be run by hVivo, a spinout from Queen Mary University of London that was bought earlier this year by Open Orphan, a Dublin-based pharmaceutical research organisation.

…The petition organiser of 1Day Sooner in the UK is 18-year-old Alastair Fraser-Urquhart who is devoting his time to the campaign before going to University College London to study cancer biology next year.

All hail Alastair Fraser-Urquhart!

This part enraged me:

The NIH is also investigating the technical and ethical requirements for challenge trials. But Nadine Rouphael, a leading vaccine researcher at Emory University in Atlanta and one of several scientists who are keen to carry out challenge studies in the US, said: “There is no urgency at NIH. The UK is well ahead — and that’s great.”

No urgency!!! I raised challenge trials with the administration in April.

Addendum: Previous MR posts on challenge trials. And here is the UK petition and the Canadian petition from 1daysooner.

Oxford’s Jenner Institute to Prepare for Challenge Trials for COVID-19

I am one of the signatories to an open letter from 1DaySooner on challenge trials sent to Dr. Francis Collins at NIH. A major development announced with the letter is that 1Day Sooner and Oxford’s Jenner Institute are collaborating to prepare viral production for use in challenge trials.The Jenner Institute is the creator of the AstraZeneca produced vaccine, the vaccine farthest along in development.

A key goal of the letter is to encourage the NIH to start its own preparation for challenge trials:

The undersigned urge the U.S. government…its allies, international funders, and world bodies (e.g. the World Health Organization), to undertake immediate preparations for human challenge trials, including supporting safe and reliable production of the virus and any biocontainment facilities necessary to house participants.

Among the signatories are 15 Nobel prize winners including Oliver Hart and Al Roth, Molecular geneticist Mario Capecchi, professor of medicine William G. Kaelin and physician Barry Marshall (who knows a thing or two about volunteer trials.)

As I discussed earlier, since challenge trials restrict the volunteers to be young and healthy, you can’t apply their results directly to the sick and elderly (the external validity problem) but “challenge trials could help us whittle down [candidate vaccines]… to the best two to three, substantially speeding up the vaccine discovery process.” You could also use challenge trials to help figure out the right dosing which is unusually important in the current situation because if a vaccine can work with .5ml instead of 1ml that’s equivalent to doubling the available supply. The Director of the Jenner Institute, Adrian Hill, agrees writing:

We see considerable potential in the use of human challenge studies to accelerate COVID-19 vaccine development, down-select and help validate the best candidate vaccines, and optimise vaccination approaches.

You can read the whole letter here.

The NIH Should Run Human Challenge Trials for COVID

As I have been warning, social distancing measures are making it more difficult to test COVID vaccines even as the cost of COVID remains very high.

WashPost: The Oxford group earlier boasted that it had an 80 percent chance of developing an effective vaccine by September. Hill said the difficulty of testing the vaccine in Britain may mean there’s only a 50 percent chance of success within that time frame now.

The probability of an Oxford vaccine by September has fallen by 30 percentage points. Oxford isn’t the only vaccine and we may be able to find clinical trial candidates in Brazil and the United States where infections continue to occur. So let’s be generous and convert this into say a 10% increase in a one month’s delay of any vaccine. The world economy is losing $375 billion a month so this means we have lost an expected $37.5 billion. That number highlights why we should be willing to pay large sums to speed vaccines and it also indicates the immense value of human challenge trials.

More than 28,000 people have already volunteered to be part of a challenge trial and if we paid a few hundred volunteers a million dollars each it would be worthwhile (and would surely increase the number of volunteers).

The main impediment to human challenge trials appears to be skittish firms rather than bureaucratic governments which is why challenge trials should test multiple vaccines under the auspices of the NIH. The NIH umbrella can protect the firms and increase the efficiency of the trials.

Addendum: China is adopting a bold approach. We used to be bold. Apathy is killing us.

Vaccine Testing May Fail Without Human Challenge Trials

In Why Human Challenge Trials Will Be Necessary to Get a Coronavirus Vaccine I asked, “What if we develop a vaccine for COVID-19 but can’t find enough patients–healthy yet who might get sick–to run a randomized clinical trial?” Exactly that problem is now facing the Oxford vaccine in Britain.

An Oxford University vaccine trial has only a 50 per cent chance of success because coronavirus is fading so rapidly in Britain, a project co-leader has warned.

…Hill said that of 10,000 people recruited to test the vaccine in the coming weeks — some of whom will be given a placebo — he expected fewer than 50 people to catch the virus. If fewer than 20 test positive, then the results might be useless, he warned.

As I wrote, “A low infection rate is great, unless you want to properly test a vaccine.” Challenge trials have issues of external validity and they take time to setup properly but they produce results quickly and they can be especially useful in whittling down vaccine candidates to focus on the best candidates.

1DaySooner now has over 25 thousand volunteers from over 100 countries.

Human Challenge Trials

What if we develop a vaccine for COVID-19 but can’t find enough patients to run a randomized clinical trial? It sounds absurd, but this problem has happened in the past. Ebola was identified in 1976, and candidate vaccines were proven safe and effective in mice and primates in 2004 and 2005, respectively. But no human vaccine was produced [at that time] because it was extremely difficult, bordering on impossible, to trial an Ebola vaccine. The problem? Ebola is so deadly that people take precautionary measures long before a vaccine can be tested.

A few pieces have been written about human challenge trials, clinical trials in which healthy people are infected with a disease in order to see if a treatment or vaccine works, but most of them focus on the ethical issues. I don’t think there are serious ethical issues so writing at The National Interest I focus on why challenge trials are useful statistically and why they may even be necessary.

Even health care workers, however, have a low enough infection rate that you either need many months to determine if there is a significant effect, or you need large populations. In Italy, about 6,000 doctors were infected over two months, out of a population of about 241,000 Italian doctors. This is a monthly infection rate of 1.2 percent. If the vaccine is 50 percent effective, then to detect this within a month, you need a sample size of 7,776 people equally divided between a vaccinated group and a non-vaccinated group. You could run the test in a smaller sample of 1,322 but then the trial would take six months. A more effective vaccine would make detecting an effect easier, but flu vaccines work at 40 to 60 percent effectiveness, so an assumption of 50 percent is not unreasonable.

But will Italian doctors still be getting infected at a rate of 1.2 percent per month when a vaccine becomes available for trial in six months or a year? We hope not. The hope is that social distancing and the use of personal protective equipment will have greatly lowered the infection rate. A low infection rate is great, unless you want to properly test a vaccine.

…The virtue of a challenge trial is that the results would be available very quickly, within a few weeks, and using only a small population. If the vaccine is 50 percent effective, for example, then we would need around 100 volunteers or perhaps even fewer depending on how many people exposed to the virus in laboratory conditions contract the disease.

By advancing a vaccine by many months, a challenge trial could save many thousands of lives and spare the world the huge economic costs of the lockdowns and social distancing that we will be using to combat the virus.

Challenge trials, however, don’t solve all problems. In particular, to limit the risk we would want to restrict the patients in a challenge trial to be young and healthy. But that raises a problem of external validity. We also want the vaccine to be safe and effective in less healthy and elderly people which requires secondary challenge trials or field testing in that population. Nevertheless, as Athey, Kremer, Synder and myself argue in our NYTimes op-ed, the high risk of vaccine failure means that we would like 15-20 vaccine candidates and challenge trials could help us whittle this number down to the best two to three substantially speeding up the vaccine discovery process.

One more point is worth bearing in mind.

[A]n ordinary vaccine trial is not without risk—a vaccine could backfire and make the disease worse—so exposing fifty or so volunteers to the virus in a challenge trial must be balanced against exposing thousands to a potentially dangerous vaccine in an ordinary clinical trial.

Thus, the total risk may be lower with a combination of challenge trials and longer, larger field trials.

Challenge trials have a long history in medicine and their statistical advantages make them powerful and even necessary. As The Guardian notes:

Scientists, however, increasingly agree that such trials should be considered, and the WHO is the latest body to indicate conditional support for the idea.

“There’s this emerging consensus among everyone who has thought about this seriously,” said Prof Nir Eyal, the director of Rutgers University’s Center for Population-Level Bioethics in the US.

Human Challenge Trials for vaccines

From an anonymous reader:

As you are of course aware, testing on vaccines for Covid-19 are beginning to be undertaken. The scientific community has seemingly decided that Human Challenge Trials (HCT) where test subjects are directly exposed to the virus following vaccination are unethical, instead using the typical protocol of vaccine/placebo inoculation followed by months of observation in order to observe effectiveness. This seems to me a grave moral error based on the following argument.

1) There exists a large cohort of young, healthy, fully informed, willing participants who would undergo HCT.

2) Given the mortality profile of this disease, these participants would be undertaking an exceptionally small mortality risk (perhaps 5-10 per 100k, based on data from Spain/Italy/NYC, assuming zero vaccine effectiveness).

3) Society deems acceptable other activities with much higher fatality risk (at least 5-10x) in both professional (soldiers, logging workers) and recreational (motorcycling, mountaineering) capacities.

4) HCT would speed up the vaccine testing process by many months, saving tens of thousands of lives and avoiding enormous economic damage.

5) HCT actually poses significantly less risk to participants in terms of allergic reaction or ADE risk compared to a standard testing protocol since the number of participants could be much smaller and they would be medically observed.

I fail to find any ethical justification for the current stance of the medical community, from either a utilitarian or deontological perspective, and believe a highly consequential error is being made. This error may be based on false analogies to past unethical testing practices in history where participants were not informed or willing and danger was significant. The current case bears no ethical resemblance, in my judgement, to these past cases.

The simplest model of such errors is that many members of the biomedical establishment do not wish to have bad feelings about any “sins of commission” and to see their status lowered as a result of “dirty hands,” and the readily criticized logistics of Human Challenge Trials.  Since HCTs do not “feel right” to them, they self-deceive into associating that feeling with a concern for the greater public good.

You should not be surprised to see grave moral errors committed in a crisis, however.  Our “mainstream” protection against grave moral errors, in normal circumstances, simply is that usually we are not given the opportunity to commit them.

I do understand that a Human Challenge Trial does not necessarily suffice to show that a given vaccine is safe.  Nonetheless it should be in the “armor of our discourse,” so to speak, as a morally acceptable alternative.  So if you are a biomedical professional, or a public intellectual, I hope you will speak up.

Here is a Matt Yglesias piece on the urgency of developing a vaccine as quickly as possible.  Eric Weinstein notes that women risk their lives every time they proceed with having children.

Fractional Dosing Trials Now!

Fractional dosing has the potential to massively increase the supply of COVID vaccine. The Moderna Phase I clinical trial and Pfizer Phase I/II trials already indicated a substantial immune response with smaller doses but the vaccine companies are under-incentivized to run additional fractional dosing trials (they won’t gain trillions, at best they will gains billions and might even lose some profit) and governments and private organizations are not picking up the ball. There are just two small trials underway that I am aware of:

N.B. now that we know that the vaccines work. we don’t need to study every dosage for efficacy against the virus. Instead of efficacy studies we can study how the vaccine is working in the body compared to those fully immunized, immunogencity trials (which is what the above trials are doing) and then use data and theory to infer effectiveness. If we felt it necessary to study effectiveness, human challenge trials would be ideal in this situation as you can study gradually smaller doses with little risk to the patients. But given the urgency, immunogenicity trials should provide enough information to make decisions on the ground. To limit risk, one could do a half-dose on the second dose or one could do a half-dose in people under the age of 50. Both of these regimens would still create significant increases in supply. Recall that in 2018, facing a yellow fever epidemic and a shortage of vaccine, Brazil used 1/5th doses to break the epidemic.

There are no guarantees but the world is ignoring a potential trillion dollar bill lying on the sidewalk.

Hat tip for discussion: Witold and Amrita.

How to Vaccinate and Continue Clinical Trials

According to Helen Branswell writing at STAT:

There are serious signs the Food and Drug Administration is getting cold feet over the notion of issuing emergency use authorizations to allow for the widespread early deployment of Covid-19 vaccines.

…“We are concerned about the risk that use of a vaccine under an EUA would interfere with long-term assessment of safety and efficacy in ongoing trials and potentially even jeopardize product approval,” Gruber said. “And not only the first vaccine, but maybe even follow-on vaccines.”

This is nonsense. There are many ways to conduct clinical trials while releasing a vaccine—indeed, we can make the clinical trials better by randomizing a phased release. Suppose we decide health care and transit workers should be vaccinated first. No problem–offer the workers the vaccine, put the SSNs of those who wants the vaccine into a hat like draft numbers, vaccine a randomly chosen sub-sample, monitor everyone.This is the well known lottery technique for measuring causal effects often used in the school choice literature. If we use this technique we can greatly increase sample sizes and as we study each wave we will gather more confidence in the data. We won’t have enough vaccine in November to vaccinate everyone or probably even all health care and transit workers so a lottery is an ethically fair as well as statistically useful way to distributed the vaccine. We can also randomize across cities and regions.

Tyrone, never one to mince words, also has good suggestions:

First, they could simply pay people to partake in those trials.  Isn’t that in essence what the NBA did with its Covid testing in the bubble?  If the value of those clinical trials truly is so high, it should be possible to internalize enough of those benefits to encourage participation.  If institutional barriers stand in the way there, let’s obsess over fixing those.

Why should we force so many Americans to be sacrificial lambs, just to subsidize the trial costs?  Let those costs be taken out of grant overhead!  (And admin. salaries, if need be.)

…Second, there is another way to keep the trial up and running.  Approve use of the treatment, but allow the suppliers to charge very high prices!  Better yet, use the law to make them charge high prices and if need be forbid insurance coverage.

Or we could use human challenge trials. The ethical objections to such are now looking more and more like nonsense as thousands of people die weekly.

In short, the idea that releasing a vaccine in phases is a threat to clinical trials is a dangerous and false dichotomy and another example of how our leaders lack vision, imagination, and courage.

Failing the Challenge

CNN says “In one word, this is why there likely won’t be a vaccine available before Election Day: biology.” Wrong. The one word is complacency. What CNN refers to as biology is the time it takes to run clinical trials.

Here’s how the trials work: You take 30,000 people, give half of them a vaccine and half of them a placebo, which is a shot of saline that does nothing. Then those 30,000 people go about their lives, and you wait to see how many in each group become infected and sick with Covid-19, the “endpoint” in medical parlance.

That waiting takes time, especially since the coronavirus vaccines currently being studied in the US are two-dose vaccines with each dose several weeks apart.

But it gets worse because trial volunteers are not random:

“Who’s in the trials – the kind of people who tend to stay at home or the kind of people who attended the Sturgis rally?” said John Moore, an immunologist at Weill Cornell Medicine, referring to a motorcycle rally in South Dakota that led to at least dozens of cases of Covid-19.

Historical precedent, as well as the demographics of the participants in the current coronavirus vaccine trials, suggest more the stay-at-home type.

That does not bode well for bringing the trials to a speedy conclusion.

Typically, those who volunteer for clinical trials tend to be “White, college-educated women,” said Frenck, who has been the principal investigator on dozens of vaccine clinical trials, and has served on the Data and Safety Monitoring Board for many others.

All three of those factors are potentially bad news for the coronavirus clinical trials, because data indicates White college-educated women are at lower risk for being exposed to the novel coronavirus.

None of this, however, is actually about biology. It’s about complacency. We could have run human challenge trials and paid for diverse volunteers but we decided that was too risky or too new or too radical or too something and so thousands of people die every week as we wait.

Addendum: Previous posts on challenge trials.

Peremptory Challenges

During the jury selection process, attorneys may request that a potential juror be stricken for cause, e.g. the juror is related to the defendant. Attorneys also have a limited number of peremptory challenges, typically between 3 and 20 depending on the state and the seriousness of the charges, which are essentially accepted without question. In Batson v. Kentucky the Supreme Court ruled that peremptory challenges may not be based solely on race but it’s widely acknowledged that Batson has no teeth because attorneys can easily come up with pretexts–which need not rise to the level of causes–to strike.

Next month the Supreme Court will revisit peremptory challenges and race. I don’t have strong opinions on the issue, although a small number of peremptory challenges seem fine to me, if only to keep the system moving and reduce the time and resources spent on jury selection. One reason I don’t have strong opinions is that I don’t think peremptory challenges are as biased as a NYTimes article seems to suggests.The NYTimes article, for example, never mentions that defendants also get peremptory challenges!  A second more subtle reason is that diversity of the jury pool constrains the jury even when there are no minorities on the jury. Here, from an earlier post, I comment on the findings of The Impact of Jury Race in Criminal Trials:

What the authors discover is that all white juries are 16% more likely to convict black defendants than white defendants but the presence of just a single black person in the jury pool equalizes conviction rates by race. The effect is large and remarkably it occurs even when the black person is not picked for the jury. The latter may not seem possible but the authors develop an elegant model of voir dire that shows how using up a veto on a black member of the pool shifts the characteristics of remaining pool members from which the lawyers must pick; that is, a diverse jury pool can make for a more “ideologically” balanced jury even when the jury is not racially balanced.

Thus, diversity of the jury pool may be as important as diversity of the jury–in a way that’s fortunate since it’s easier to make the jury pool diverse (as we have done with required randomization) than the jury. Instead of eliminating peremptory challenges, I’d raise their cost. For example, suppose that both sides get 3 “free” peremptory challenges but if they wanted one more they would have to give two to the opposing side.

Addendum: Justice Kavanaugh has written in favor of restricting peremptory challenges.

The Impact of Jury Race in Criminal Trials

In a great paper, The Impact of Jury Race in Criminal Trials, Shamena Anwar, Patrick Bayer and Randi Hjalmarsson exploit random variation in the jury pool to estimate the effect of race on criminal trials. The authors have data from nearly 800 trials in two Florida counties. On any given day, a jury pool is randomly drawn from a master list based on driver’s licenses. On some days, the pool of about 30 people contains some black members and on other days, purely for random reasons, it does not. The voir dire process–>For every $1 spent on legal aid, the savings can range from $1.60 to $30.removals, excuses and challenges–whittles down the jury pool to 6 jury members with typically 1 alternate.

The authors have data on the race, gender, and age of each member of the jury pool as well as each member of the ultimate jury. The authors also know the race and gender of the defendant and the charges. What the authors discover is that all white juries are 16% more likely to convict black defendants than white defendants but the presence of just a single black person in the jury pool equalizes conviction rates by race. The effect is large and remarkably it occurs even when the black person is not picked for the jury. The latter may not seem possible but the authors develop an elegant model of voir dire that shows how using up a veto on a black member of the pool shifts the characteristics of remaining pool members from which the lawyers must pick; that is, a diverse jury pool can make for a more “ideologically” balanced jury even when the jury is not racially balanced.

The author’s results show not only that blacks and whites are treated differently depending on the composition of the jury pool but also that random variation in the jury pool adds to the variability of sentences holding race constant. Like is not treated as like. The results also suggest that we don’t need racial quotas to increase fairness. We can increase fairness and reduce variability in a racially neutrally way by expanding the size of juries. Six-person juries have become common because they are cheap(er) but a return to twelve person juries would reduce the variability of sentences and greatly equalize conviction rates across race.

What I’ve been reading

1. Dan Werb, The Invisible Siege: The Rise of Coronavirus and the Search for a Cure.  An excellent book on the history of coronaviruses more generally, with much of the strongest material coming on how earlier coronavirus investigations fed into the progress we have made on Covid-19.  Recommended, not just what all the other Covid books are telling you.

2. James Poskett, Horizons: The Global Origins of Modern Science.  A useful account of what the title promises, with a look at contributions from pre-conquest Mexico, China, and other non-Western locales.  Maybe the book pushes the non-Western theme a little too much at points, but this is basically a sane and readable account, and most of the cross-cultural connections are valid rather than strained.

3. Evan Lieberman, Until We Have Won Our Liberty: South Africa After Apartheid.  An interesting book, and one which contains a lot of useful information.  Yet the author works too hard to avoid recognizing just how badly matters have gone.  Overall, incomes are down and the racial wealth gap has not improved…and that is after getting rid of one of the most inefficient economic systems of all time, namely apartheid.  For sources try this and this, among others.  The income gains you can find are focused in a super-small group.

4. Paul Mango, Warp Speed: Inside the Operation that Beat Covid, the Critics, and the Odds.  Written by an HHS insider and participant, this is kind of cheesy and fanboyish.  But probably it should be!  For one thing, the book gives you a sense of just how much talent was involved in OWS, an under-discussed lesson.  On p.69, you can learn that they repeatedly considered human challenge trials and learn their question-begging reasons for refusing to do them.

5. David Hackett Fischer, African Founders: How Enslaved People Expanded American Ideals.  An extended history of U.S. slavery, focusing on regional differences, for instance Carolina Gullahs vs. New Orleans vs. Mississippi.  As you might expect, the broader story is integrated with that of the particular African origins of the slaves as well.  A strong book, recommended.

Michael Magoon’s From Poverty to Progress: Understanding Humanity’s Greatest Achievement is a very good introduction to the importance of progress and material wealth in history.