I have now completed listening to Polio, An American Story by David M. Ochinsky which I purchased from Chirp (see review).(1) I was amazed by the number of lessons and changes that occurred in biomedical research and our policies related to public relations, ethics, and people with disabilities, outlined by the author. It’s a lot to present here, and certainly if you want a thorough and complete treatment please read Polio. In part 1 I will discuss:
- Increasing scale of clinical research
- Changing ethics of research
In part 2 I will discuss:
- Developing sources of research funding
- Funding for public health initiatives by government
- Evolving status of intellectual property for vaccines
- Organizing for respect for people with disabilities
Increasing scale of clinical research
Below I consider that the Salk polio vaccine was one of the first double blind controlled clinical trials setting a standard for future trials, and that this trial still remains the largest public health research clinical trial run in the U.S.A.
One of the first double blind controlled clinical trials
The protocol for the Salk vaccine 1954 clinical trial required approval by a vaccine advisory committee of the National Foundation for Infantile Paralysis (now the March of Dimes Foundation) chaired by Thomas Rivers, a leading virologist now considered the father of modern virology. Joseph Bell, an epidemiologist at the National Institutes of Health who served as scientific director on the vaccine study insisted that the trial be double-blinded. This would be a study that neither the child receiving the injection nor the person giving it would know whether the child received the vaccine or a placebo. Information would be coded so only the people running the trials would know which codes were associated with which treatment. This characteristic of the Salk vaccine trial ensured that the study would be evaluated without the pressure and bias of knowing which child received which solution, and they could not change the randomness of the study by providing the real vaccine injections to their favored patients. It also added credibility to the results. However, it did mean that the trial would require twice as many participants, and the record keeping and surveillance would be unlike any previous trial. Thanks to Joseph Bell, this study was was the first major clinical trial to include this double-blind procedure, and as a result Bell would go on be honored for making double-blind clinical trials his contribution to the research community.(2)
The largest public health clinical trial in the U.S.
What was most recognized by the NY Times in the 1995 obituary of Jonas Salk (3) was that he ran the largest public health clinical trial with 1.8 million children and adults participating. A total of 1,349,135 children were included in the study. Approximately 420,000 children received the vaccine, another 200,000 received a placebo, and the remaining children in the study were observed for whether they came down with polio as the observation control. Another 450,000 adults were also observed for this study. All participants in the study needed to have separate records – paper, not electronic in 1954. Of those receiving injections, 95% got all three vaccinations, a measure of the success of the study organization. Furthermore this clinical study was done in record time, between April 26, 1954 and April 12, 1955, including the treatments and analysis!
Seven million people volunteered their time and two thirds of the nation had donated to the March of Dimes by 1954. For the trial, tens of thousands of volunteers were trained. The study probably involved tens of thousands of school principals and teachers for record keeping and contact with parents, physicians and nurses to run vaccine clinics, as well as hundreds of thousands of non-professional volunteers to gain public participation. To support this effort more than 200 counties put on a two-day workshop to plan the trial. Thomas Francis, a virologist and epidemiologist based at the University of Michigan, deserves kudos for his planning and executing this successful trial, Basil O’Connor for supporting this effort through his National Foundation for Infantile Paralysis, and, Jonas Salk for providing the vaccine and standards for its purification and testing to ensure that it lacked live virus which could infect children receiving the vaccine.
Changing ethics of research
Coming after the Nuremberg Code in 1947 (4) but before both the Declaration of Helsinki in 1964, as well as its update in 1975 (5), and the Belmont Report in 1979 (6), the large polio research trials were at the cutting edge of the development of the changing policies in research ethics. Here I point out some of the learnings related to consenting, use of prisoners, self-treatment as a first test of safety, and the ethics of controlled trials.
For the Salk vaccine study in 1954, millions of parents were asked to risk the health of their children by participating in this study. The consent form stated:
“This is one of the most important projects in medical history. It’s success depends on the cooperation of parents. We feel sure you will want your child to take part.”Oshinsky, David M. Polio: An American Story. U.S.A.: Oxford University Press, 2005. https://www.recordedbooks.com/title-details/9781428129856.
Parents were informed that their child may not be fortunate enough to receive the vaccine, and may receive the placebo, or may be one of the observed children. Risks were mentioned, but dismissed quickly. Maybe with more confidence than many in the scientific field thought of killed virus vaccines, the parents were told that the vaccine “cannot cause the disease” using the previous study on 5,000 volunteers including Salk, his wife and three sons, as further proof of the vaccines safety.
Specific regulations and oversight became necessary in doing Federally-funded human studies research following the uproar about maybe the most controversial human subjects study in the U.S.A., the disturbing story of the Tuskegee Syphilis Experiment (7) which came to light in the early 70’s and resulted in the National Research Act of 1974 (8) which established Institutional Review Boards (9) and led to the Belmont Report giving further guidance for human studies research regulation. (7) Based on my experience with human studies Institutional Review Boards, much of the 1954 polio vaccine research participation consent form would have needed to be rewritten today, and though this might have effected how quickly the study completed, I think it still would have gotten the numbers they needed to prove a significant effect of the vaccine.
Use of prisoners
Albert Sabin tested his live-virus vaccines on 200 prisoners at the federal prison in Chillicothe, Ohio, after testing the same vaccine production lot in monkeys and chimpanzees to show their safe use. Sabin obtained approval for this study with institutionalized adults in prisons after receiving rejection for using institutionalized children. The study was successful with no infections resulting, and every vaccinated prisoner developing antibodies. These prisoners were promised reduced sentences and additional privileges – a sure strategy for obtaining consent. (1) Prisoners were used in research from at least 1914 in the U.S.A. until the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research made the recommendation for a moratorium on prisoner experimentation in 1976. (10) The concern raised is the issue of comparative justice – that the risks and benefits of a study should be equitably distributed across different types of subjects, and a prisoner community does not insure this distribution. Compared to free subjects, prisoners live in a coercive environment so their choices are more limited, and the benefits from treatment are less, and the quality of healthcare received is less. Thus prisoners were excluded from all experimentation unless the study posed minimal risk and did not directly improve health or well-being of prisoners under study. (11)
An standard going back centuries still held in the first half of the 20th century was self-treatment. This demonstrated the confidence researchers in the safety of their drug or vaccine, increasing their ability to convince others to become subjects. John Kolmer, William Park and Maurice Brodie, all tested their polio vaccines on themselves in the 1930s. Polio researcher Hilary Koprowski first tested a live polio virus vaccine on himself in 1948. Then Jonas Salk tested his killed polio virus vaccine on himself and his three children in early 1954 as part of the mini-field trial with hundreds of children in the Pittsburgh area. The lack of infections was used as an argument against publicity that the vaccine was not safe. (1) Apparently self-experimentation is still not uncommon, but it is generally frowned upon by the scientific community and funders of research. It remains alright for researchers to treat themselves, but not to their lab employees, since the NIH has had policies since 1954 (maybe triggered by the Salk experimentation) restricting use of employees as research subjects (12).
Ethics of controlled clinical trials
Controlled trials, though absolutely necessary for the proof of effectiveness of a vaccine, as demonstrated by the quick acceptance of the positive results of the Salk vaccine trial completed in April 1955, are ethics challenges because it is always difficult to, even if blindly, put a child on a placebo treatment when the vaccine could work effectively, but without the placebo we would not have the proof. It’s interesting to note that the Sabin live-virus vaccine was part of the largest clinical study ever run world-wide. It was run with 10 millions soviet children in Russia.
Having written plenty already about the lessons learned from the development of a polio vaccine, with much more yet to go, I decided to leave the remainder for part 2.
- Oshinsky, David M. Polio: An American Story. U.S.A.: Oxford University Press, 2005. https://www.recordedbooks.com/title-details/9781428129856.
- Chalmers, Iain. “Joseph Asbury Bell and the Birth of Randomized Trials.” Journal of the Royal Society of Medicine 100, no. 6 (June 2007): 287–93.
- Jr, Harold M. Schmeck. “Dr. Jonas Salk, Whose Vaccine Turned Tide on Polio, Dies at 80.” The New York Times, June 24, 1995, sec. Obituaries. https://www.nytimes.com/1995/06/24/obituaries/dr-jonas-salk-whose-vaccine-turned-tide-on-polio-dies-at-80.html.
- “Nuremberg Code.” In Wikipedia, May 18, 2020. https://en.wikipedia.org/w/index.php?title=Nuremberg_Code&oldid=957363157.
- “Declaration of Helsinki.” In Wikipedia, May 21, 2020. https://en.wikipedia.org/w/index.php?title=Declaration_of_Helsinki&oldid=958017318.
- HHS.gov. “Read the Belmont Report.” Text, January 15, 2018. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html.
- “Tuskegee Syphilis Experiment.” In Wikipedia, June 6, 2020. https://en.wikipedia.org/w/index.php?title=Tuskegee_syphilis_experiment&oldid=961032307.
- “National Research Act.” In Wikipedia, October 4, 2019. https://en.wikipedia.org/w/index.php?title=National_Research_Act&oldid=919512772.
- “Institutional Review Board.” In Wikipedia, April 17, 2020. https://en.wikipedia.org/w/index.php?title=Institutional_review_board&oldid=951507723.
- U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1976b. Research Involving Prisoners: Report and Recommendations. DHEW publication no. (OS) 76–132. Bethesda, MD: Author.
- “Prisoners as Research Subjects | Encyclopedia.Com.” Accessed June 12, 2020. https://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/prisoners-research-subjects.
- Landhuis, Esther. Dec. 5, 2016, at 12:30 PM. “Do It Yourself? When the Researcher Becomes the Subject.” Science | AAAS, December 2, 2016. https://www.sciencemag.org/careers/2016/12/do-it-yourself-when-researcher-becomes-subject.
- Edwards, Sarah J L, R J Lilford, and J Hewison. “The Ethics of Randomised Controlled Trials from the Perspectives of Patients, the Public, and Healthcare Professionals.” BMJ : British Medical Journal 317, no. 7167 (October 31, 1998): 1209–12.