You will often hear people asserting that the United States has “the best health care in the world.” If you look at the data, however, the United States spends more per capita on health care than other peer countries while having one of the lowest performance rankings.
The “inefficiencies” in the United States health care system cited in studies like this one, in reality, represent huge profits for drug companies, medical device manufacturers, insurance companies, and hospitals.
What these people mean is that the United States has the most advanced medical research and development environment in the world, resulting in the most advanced medical treatments in the world. The wealthiest 1% in the United States can afford to buy the best health treatments, while the vast majority of lower-income Americans can’t afford co-pays, deductibles, and premiums, if they can afford medical insurance at all.
This system depends in large part on government-funded research at the largest research hospitals in the world, tested on volunteers (many of whom are from the lowest economic strata in this country). This may sound familiar when I describe the Justice Principle in a moment.
The bottom line here is that research does not just happen by itself, which means progress in the advancement of important medicine does not just happen by itself. Medical research requires tax dollars and willing human subjects who must be protected.
The Belmont Principles
When Dr. Harmatz and his co-authors said their “procedures [were] in accordance with the [IRB] subjected to the United States FDA’s IRB regulations, and the ethical standards of the Declaration of Helsinki,” what exactly did they mean?
To appreciate this statement, you need to understand some history.
The Declaration of Helsinki derives from the Nuremberg Code following the end of World War II, where the Allies discovered truly horrific research experiments that the Nazis had performed on prisoners of war without their consent. The Nazis didn’t see these prisoners as humans, so they didn’t care what they did to them as long as the Nazi scientists learned things beneficial to the Germans. These experiments were considered war crimes and the world was so appalled that it collectively vowed never to forget and never to let this happen again. They made a public declaration to that effect in 1964.
In the United States, a medical experiment known as the “Tuskegee Study of Untreated Syphilis in the Negro Male” began in Alabama in 1932. Doctors were able to study the progression of untreated Syphilis in these low-income African-American male subjects because the researchers purposely withheld informing of and providing a new and efficacious treatment (penicillin) from them to observe the suffering and death resulting from the impact of the disease on these human bodies. The public wasn’t made aware of these experiments until 1972. The United States Government even apologized for this wrong.
“The United States government did something that was wrong — deeply, profoundly, morally wrong… It is not only in remembering that shameful past that we can make amends and repair our nation, but it is in remembering that past that we can build a better present and a better future.”
— President William J. Clinton, 1997 re: the Tuskegee study
In 2010, the United States Government again apologized for sponsoring experiments similar to Tuskegee, this time from 1946 to 1948 and performed on Guatemalan citizens with the cooperation of health officials in Guatemala. Did I mention Maria Isabel Bueso is from Guatemala? Don’t forget this point.
The National Research Act was passed in 1974, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which met in Belmont, CA. The Commission met in 1976, reviewing and discussing dozens of papers and presentations by experts from around the world. In 1979 they published, “The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research.”
Based on these many historical instances of unethical treatment of human subjects of research, the United States Government adopted Title 45, Part 46, of the Code of Federal Regulations (known colloquially as the “Common Rule”) mandating that the principles laid out in the Belmont Report be followed for all federally funded research in the United States involving human subjects.
The Belmont Principles are Respect for Persons, Beneficence, and Justice.
Respect for Persons
The thing about research most people are familiar with, following the cases laid out just a moment ago, is the idea of informed consent. Research subjects should be told about the procedures they will undergo, the potential risks, the potential benefits, and what kind of modest compensation they will receive to enable their participation (e.g., parking expenses and compensation for time spent in extended lab visits.) They are not to be coerced, lied to, or forced to be involved in anything to which they don’t agree.
It also protects those with diminished capacity, or who otherwise cannot knowingly consent for themselves. Examples of this are minors, whose parents or legal guardians can consent for them, someone who is unconscious or has a limited mental capacity from disease or birth defects.
The idea of beneficence can be stated simply as not just avoiding harming the research subject, but carefully and systematically balancing the risks the subject will face with the larger benefits to society that hopefully result from the research.
This isn’t about benefits to the research subject, for a couple of reasons.
Experimental treatments may not work, so subjects should not expect their voluntary participation will save their life or cure their disease. It may not.
Valid scientific studies may require that the researcher and the subjects both be unaware of which subjects are control subjects — subjects who receive a placebo, meaning no treatment at all — to avoid biases resulting from knowing when the experimental treatment is present.
Every week, Bueso receives an intravenous infusion of medicine at a hospital in Oakland. Her doctor said the treatments have extended her life many years beyond what Guatemalan physicians had predicted when Bueso was a child.
Without the weekly treatment replenishing the missing enzyme, Bueso would die in six to 12 months, said Dr. Paul Harmatz, a pediatrician at UCSF Benioff Children’s Hospital and Bueso’s physician.
In situations like Isabel’s, where receiving no treatment may hasten her death, the risks associated with being randomized into the control group are real and serious. Pretend for a moment that you are Isabel as you read this:
The patient, an 11-year-old Hispanic female, was treated with rhASB in an open-label extension of a 24-week randomized double-blind study evaluating the safety and efficacy of rhASB. […] The patient received placebo during the double-blind portion of the trial and began rhASB during the open-label extension study. She was followed for two years.
Koseoglu, S.T., Harmatz, P., Turbeville, S. et al. Int Ophthalmol (2009) 29: 267. https://doi.org/10.1007/s10792-008-9213-7
The anticipated benefits from the study in which Isabel was involved were expected to be great. The FDA (read “the United States Government”), was happy to have Isabel volunteer to be a research subject to benefit the citizens of the United States.
The FDA granted this application Fast Track designation, which seeks to expedite the development and review of drugs that are intended to treat serious conditions where initial evidence showed the potential to address an unmet medical need. Mepsevii also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The hospital and the drug company involved were also happy to have Isabel involved in the study and its benefit to citizens of the United States (and future profits to each, as we are a capitalist economy, after all.)
“We are proud to be part of this groundbreaking trial and it is our hope that the gene editing therapy will produce benefits to our patient and other MPS patients that will greatly contribute to an improved quality of life. We are grateful to our patient Brian for being the first person to participate in the trial,” said Dr. Harmatz, M.D., a pediatric gastroenterologist and a principal investigator for the CHAMPIONS study at the UCSF Benioff Children’s Hospital Oakland.
“For the first time, a patient has received a therapy intended to precisely edit the DNA of cells directly inside the body. We are at the start of a new frontier of genomic medicine,” said Dr. Sandy Macrae, CEO of Sangamo Therapeutics.
It may seem obvious on its face that the Justice Principle involves fairness. Yes, but it’s more involved than that.
Each person deserves equal consideration in how they are to be treated. Just like Respect for Persons, this is to be universal, not biased or purposefully discriminatory.
The benefits that result from research should be distributed fairly according to individual need, effort, societal contribution, and merit. It is unethical to put all the burden on prisoners, for example, and only give the benefits to the well-off.
The selection of subjects should be fair, and the burdens should be allocated equitably across all involved subjects.
John Rawls came up with a test of fairness he called the “Veil of Ignorance” that fits the attributes of Justice I just recited. The idea may resonate with the more familiar concept of the Golden Rule (“Do unto others as you would have them do unto you,” something that religious leaders used to instill in us all as a virtue):
“When contemplating a moral action, imagine that you do not know if you will be the moral doer or receiver, and when in doubt err on the side of the other person.”
— Michael Shermer, The Moral Arc: How Science and Reason Lead Humanity Toward Truth, Justice, and Freedom