The procedure room smells of disinfectant. The man in the white coat, sitting on a stool, keeps up a reassuring patter as he swabs the skin of the old man. “I am Dr. Southam,” he says. “I’m going to clean a spot on your leg with some alcohol.”
Southam takes a small syringe from the stand. “This is Novocain, it doesn’t hurt, you’ve had it before.”
There is no suggestion that this unfamiliar procedure is not part of the patient’s routine care. If the man demands to know what is being done, Southam has a ready explanation. “I’m going to inject some cells to test your immune system.” Southam takes a second syringe from the tray and deftly injects a small amount of cloudy fluid just under the skin.
The year was 1963; the cloudy fluid contained live cancer cells. 1
Scandal at the Jewish Chronic Disease Hospital
Southam was from the Memorial Sloan Kettering Cancer Center in New York; his experimental subjects were patients in the Jewish Chronic Disease Hospital. The purpose of the experiment was to learn more about the body’s natural immunity to cancer—a topic as important today as it was fifty years ago. As Southam predicted, the patients’ immune systems quickly rejected the cancer.
The men were unharmed but their rights had been grievously violated. Other doctors in the hospital were shocked and word of the scandal spread rapidly; widespread negative publicity and a lawsuit soon followed. Ultimately, Southam’s unethical research played a key role in persuading the US government to impose a system of ethics review to protect research subjects. 2
The ethics review system, implemented by research ethics committees (in Commonwealth countries) or institutional review boards (in the United States), was immediately successful, promoting subject safety and snuffing out unethical research. It deserves credit for this achievement.
Benefit Overwhelmed by Cost
This benefit, however, comes at a dear price. Unethical cancer research has been curbed, but ethically sound cancer research must work in handcuffs; for a sobering example, see Giving Cancer the Upper Hand.
The central problem is that boards conduct unbalanced review, focusing on risk and paying scant heed to the benefits of the research and the cost of the review. Risk management theory predicts just this failure; for details of how this failure evolved, see Research Ethics Review—A Failed System of Risk Management. This dysfunction, echoed in the regulation of many other scientific and scholarly fields, multiplies the system’s costs and leaves unchanged its benefit.
It is time to rethink how we protect subjects in research. What kind of governance would be most suitable?
Scientific research could be governed by governmental regulation or through private mechanisms. In 1963, private governance at MSK failed. In 2014, governmental regulation has also failed. We should turn again to private governance, now informed by modern concepts of risk management.
If we were to replace governmental regulation with private governance, what form would it take, and how would it function?
Risk Management Done Right
It is simplicity itself: institutions should manage the risk of research in the same way they manage risk of every other kind. Today, major organizations, including universities, companies, government agencies, and nonprofit institutions like MSK have formal risk management plans intended to promote thoughtful decisions that balance risk and opportunity. This analysis focuses on biomedical research, but the same principles would apply to research of every kind.
Risk Management at Memorial Sloan-Kettering
MSK daily manages risks of every kind: physical, human, reputational, and financial. In 2012, MSK undertook a capital campaign that increased its debt to $2.1 billion, seeking benefits it could achieve only with improved physical facilities. In response to MSK’s new indebtedness, Moody’s downgraded its debt rating, while giving MSK credit for its “top reputation for clinical and research activities.”3
That reputation is well-deserved, for MSK has a distinguished record of research. In the coming years, if MSK’s research goes well, its reputation will be enhanced, as will its ability to attract patients and borrow money at more favorable rates. If someone is harmed as a result of unethical research, the subject will not be the only one to suffer; MSK will also lose in many ways. MSK shares in the risk of research, so protecting subject welfare is in its interest.
Southam Déjà Vu
Clinical cancer results from a failure of the body’s immune system. Scientists are pouring time and effort into the development of cancer vaccines today. One hope is that someone who has early disease can be given a vaccine against their own cancer and thereby be cured; see, for instance, Cancer Immunotherapy: Moving Beyond Current Vaccines.4 Success would transform the lives of countless people with cancer.
How would MSK respond if one of its scientists wanted to replicate Southam’s experiments today? Let’s compare the reaction of MSK’s current institutional review board with that of a balanced consideration of risk and benefit by appropriate officials.
Today’s Institutional Review Board Response
There is no way to be sure what MSK’s IRB would do, but it would probably have two major concerns about replicating Southam’s experiment.
The IRB would probably debate whether any subject should be permitted to consent to the injection of live cancer cells. The committee might well prohibit the research on that ground.
The board’s second concern would have nothing to do with subject welfare. Ethics boards were created to protect subjects from harm, but they also act to protect the institution itself from lawsuits, financial loss, unfavorable publicity, and more. 5,6 Even if the board felt that subjects should be permitted to volunteer, it might fear that replicating Southam’s infamous experiment would lead to a media nightmare. Southam’s work was the most notorious in the history of the institution; I would not be surprised if the IRB said no.
Under US law, the IRB’s rejection of the research could not be overturned by MSK’s leadership.
Oversight under the New System
How would MSK decide whether to approve this research if the responsibility for subject safety were shifted from the IRB to MSK’s leadership, as modern risk management theory directs?
In principle, a well-run institution puts preliminary authority for risk management at the appropriate level, while retaining final responsibility at the highest institutional level. In practice, there are many ways to implement this approach. Because there is no single right way to manage risk, MSK would be at liberty to try one method and then tweak it over time to improve its function—something that cannot be done under the current rigid system.
Research oversight at MSK, as at other major institutions, involves multiple layers of review with multiple objectives. In this discussion, I single out review by the IRB and show how the task of protecting human subjects should be removed from the IRB and restored to MSK’s overall systems. This would not change review with regard to, for instance, scientific validity, funding, institutional priorities, or conflicts of interest. Where should MSK assign responsibility for making sure subjects are not placed at undue risk?
One promising approach would be to make each department chair responsible for research conducted within that department; each chair, in turn, could adopt a procedure suited to the department’s resources and research projects. Some departments would be small enough, and their research simple and harmless enough, that the chair could personally review and sign off on every protocol.
The Department of Medicine has a large and complex research portfolio, and it would be reasonable for the Chair to form a committee to review the research of its members. The chair could certainly nominate members of the old IRB to serve. This committee, with members only from the Department of Medicine, would be more familiar than the institution-wide IRB with the types of research the department conducts. In contrast to the IRB, the new committee would be instructed to conduct balanced review. Finally, the department chair would be free to accept or reject its recommendations.
The Department Might Say Yes
People’s perception of, and tolerance for, risk varies greatly. As Michelle Meyer has lucidly shown, the variation in risk that people will accept, and the benefit they desire, makes it difficult for ethics boards to reach sound decisions. 7
The department’s committee and chair could approve the experiment with confidence that some people would volunteer. You might shudder at the idea of getting an injection of live cancer cells under the skin of your arm, but some people would step right up.
This isn’t mere speculation. Six years before his disastrous experiments in New York, Southam sought volunteers in the Ohio State Penitentiary in Columbus to participate in cancer injections. The prison newspaper explained that volunteers would undergo the “injection of live cancer cells (taken from some person who has a cancer) into both forearms of the volunteer—by needle injection under the skin.” Southam had more volunteers than he could use.
Research ethics dogma holds that prisoners should not be used as research subjects because they are in a coercive environment, unwilling or unable to say no. But Southam’s newspaper notice was open-ended; no man was approached individually or offered a reward other than a chance to help science understand cancer. These men understood that there was a risk but they were willing, and sometimes eager, to accept it. Ralph Alvis, the warden, reported that the research “has provided all our men—the volunteers and the others alike—with a new sense of pride in our common humanity.” 8,9
MSK’s Department of Medicine might reasonably authorize a replication of Southam’s experiment, provided that the investigator make the nature and risks of the experiment crystal clear to potential subjects.
…or It Might Say No
The department’s committee might also conclude (like the IRB) that the risk of adverse publicity would be too great. The committee can see the headline: “Memorial Sloan Kettering Hasn’t Changed: Still Injecting Cancer Cells.”
Under the present regulations, an investigator who feels the IRB is mistaken is not guaranteed a right to appeal. If research were regulated properly, investigators would routinely be able to appeal, not because it should be a legal right, but because properly-run institutions recognize that senior leadership should be involved when subordinate units disagree.
The Leadership Would Have the Final Word
The MSK leadership could substitute its own perception of the risk of proceeding versus the possibility of benefit. MSK’s leadership is better connected to the media than any mid-level committee, and it enjoys the advice of experienced public relations consultants. It knows that the public is as interested in cancer research as ever, and a carefully-conducted replication of Southam’s work, modified as needed to make its results useful today, could be used to demonstrate that with proper consent we can now ethically do research that was unethical fifty years ago.
If the media covered the story favorably (which is something MSK can influence), the headline would read, “Memorial Sloan Kettering: Transformation of Research and Research Ethics.” The story would describe how today’s volunteers, fully-informed and willing to accept defined risk, are eager to help fight cancer.
Would a decision to proceed be wise or foolish? I don’t know. But this is the kind of decision that an IRB is poorly positioned to make, and senior leadership not only can, but must, make all the time.
The Old and the New
The present system of review forces every institution to conduct research oversight using a single, governmentally-required model that cannot be modified. This system has failed to produce balanced review or benefits that justify its costs.
The new approach would encourage nuanced consideration by officials at all levels of the institution, with final responsibility with the top leadership, where it belongs. Modern cancer research will be able to offer new hope to patients when we release the handcuffs that were hammered on its wrists fifty years ago.
1. Katz J, Capron AM, Glass ES. Experimentation with human beings; the authority of the investigator, subject, professions, and state in the human experimentation process. New York: Russell Sage Foundation; 1972.
2. Frankel MS. The public health service guidelines governing research involving human subjects: An analysis of the policy-making process. [PhD dissertation]. George Washington University; 1972.
3. Moody’s Investors Service. Moody’s downgrades memorial sloan-kettering cancer center’s (NY) debt rating to Aa3 from Aa2 and assigns Aa3 rating to $400 million series 2012A taxable bonds. . 2012.
4. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: Moving beyond current vaccines. Nat Med. 2004;10(9):909-915.
5. Moss J. If institutional review boards were declared unconstitutional, they would have to be reinvented. Northwestern University Law Review. 2007;101:801.
6. Stark LJM. Behind closed doors: IRBs and the making of ethical research. Chicago; London: The University of Chicago Press; 2012.
7. Meyer MN. Regulating the production of knowledge: Research risk-benefit analysis and the heterogeneity problem. Draft. 2012.
8. Brecher R, Brecher E. They volunteered for cancer. Reader’s Digest. 1958:62-66.
9. Southam CM, Moore AE, Rhoads CP. Homotransplantation of human cell lines. Science. 1957;125(3239):158-160.