Henry Knowles Beecher and the Development of Informed Consent in Anesthesia Research

Abstract

(Kopp) Assistant Professor of Anesthesiology and Pediatrics, Adjunct Assistant Professor of Social Medicine.Received from the Department of Anesthesiology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Submitted for publication September 28, 1998. Accepted for publication February 4, 1999. Supported by a 1995 Paul M. Wood Fellowship Award from the American Society of Anesthesiologists, Park Ridge, Illinois. Presented at the 1998 Anesthesia History Association Meeting, May 7, 1998, Toronto, Ontario, Canada.Address reprint requests to Dr. Kopp: Department of Anesthesiology, School of Medicine, The University of North Carolina at Chapel Hill, CB# 7010, 223 Burnett-Womack Building, Chapel Hill, North Carolina 27599-7010. Address electronic mail to: [e-mail] words: Henry K. Beecher; ethics; experimentation; informed consent; patients' rights.This article is accompanied by an Editorial View. Please see: Truog RD, Robinson W: Informed consent for research: The achievements of the past and the challenges of the future. Anesthesiology 1999; 90:1499-501.AT the end of the twentieth century, guaranteeing patients' rights and the rights of participants in clinical research are viewed as inextricably linked to the protection of all fundamental human rights. This has not always been the case. Beginning with the Nuremberg Code of 1947, global attention began to be focused on the rights of participants to freely consent and freely withdraw from any human research project. In the aftermath of World War II, the victors regarded the need to guarantee these rights as a duty that applied to the vanquished societies more so than to their own. For years after the war tribunals, conduct of government-funded research in the United States did not always satisfy the principles enunciated in the Nuremberg Code. It was largely through the efforts of one person, Henry Knowles Beecher, that the US research community recognized the need to change its attitudes and practices toward human research participants.David Rothman, in Strangers at the Bedside: How Law and Bioethics Transformed Medical Decision Making, begins chapter four stating:The career of Henry Beecher provided few clues that he would be the one to expose in most compelling fashion how the researchers in the post-World War II decade abused their discretion. Unlike many whistle blowers, Beecher stood at the top of his profession. [1]A detailed look at Beecher's life and work reveals many signs of a durable concern for the rights of patients, human subjects, and scientific purity in the conduct of research. In this article, I identify and discuss antecedents to Beecher's interest in informed consent in clinical research, review his early work on the subject, discuss the landmark article "Ethics and Clinical Research," and show its impact on medical research in general and on anesthesia research in particular.Henry Knowles Beecher, first Henry Isaiah Dorr Professor of Anaesthesia Research and Chief Anaesthetist at Harvard, had many interests during his long and illustrious career. The origins of his concern for the ethics of human research had deep scientific and humanitarian roots. His scientific concerns related to his advocacy for placebo use in randomized, prospective research trials. His humanitarian concerns related to his abhorrence of the human experiments conducted by Nazi doctors.Beecher was among the earliest investigators to note the placebo effect. Observing the inexplicable decreased need for morphine among wounded soldiers awaiting evacuation at Anzio Beachhead, he hypothesized that the body, in particular the mind, produced physiologic effects that might otherwise be wrongly ascribed to an administered drug. [2]This observation lead him to advocate placebo use in a "'double-blind' technique" and "randomization of administration of the agents tested" in clinical investigations of drugs in humans. [3]Although he was not the only proponent, he was perhaps the most persistent advocate of placebo use.A second early Beecher interest was human experimentation by Nazi doctors. After World War II, Beecher reviewed classified military documents for the US Army about human experimentation in Nazi concentration camps. He kept detailed records of these atrocities in his personal files to serve, perhaps, as a constant reminder of the actual and potential magnitude of humanity's inhumanity during the pursuit of scientific knowledge. The following excerpt, from a declassified report by Dr. (then Col.) Esmond R. Long, about Buchenwald Concentration Camp, is among Beecher's papers at the Francis A. Countway Library of Medicine, Harvard University. It illustrates Beecher's interest in how science gone awry constituted a particularly horrific form of depravity:Near the building used as a hospital was a pathological laboratory. I saw specimens of pulmonary tuberculosis, carcinoma of the lung and tattoed [sic] skin. These were put up in regular museum jars, and were unusual in no way. It was evident, however, from the attention they excited, that they were looked upon by non-medical visitors as illustrations of the depravity of the German doctors... In this building, however, it seems clear that ruthless experiments on live human beings were carried on. Dr. Ding, a well-known German clinician, is said to have tested a typhus vaccine here on human beings, by inoculating them with a vaccine and injecting them with a live virulent culture later. The experiment was unsuccessful. One report was that 900 were inoculated and 700 died. Whatever the numbers, there appears no question about the basic facts.... [dagger]From his writings, it is clear Beecher's interest in the ethics of human experimentation sharpened as a result of his work on placebos and his review of Nazi crime records. He followed the Nuremberg trials and was familiar with the Nuremberg Code. He questioned the science behind Nazi experiments conducted in concentration camps and extended the question to those conducted by other physicians and scientists. In doing so, he became convinced that a study, to be scientifically valid, must be ethical from its inception. At the same time, he came to believe that science's values were neither the highest ones to which all other orders of value are subordinate, nor that ethical considerations should be suborned to the scientific value of any given experiment. These beliefs, then, subtended his future actions as a whistle blower who would reveal his fellow researchers' ethical transgressions, relying, as he did, on the scientific and moral authority he had gained by being at the top of his profession to advance his arguments.By 1958, Beecher's thoughts on consent in human experimentation had crystallized. As early as February 10, 1958, Dr. Beecher addressed members of the Executive Committee of the Committee on Research at Harvard in a memorandum and Dean George P. Berry in a letter, expressing his concerns:It has long seemed to me that we, in common with most other similar institutions, have not faced up to the problems surrounding experimentation in man. As I have pointed out in the attached review, such errors as I at least have encountered have all been based upon ignorance or thoughtlessness or inexperience and never upon willful or unscrupulous attitude toward patients or subjects.... These matters are much too complex, it seems to me, to permit the establishment of rigid rules in most cases. I do believe, however, that a great deal can be done to correct nearly all abuses by disseminating information on past experience and thinking in this complicated field. Curiously enough, no review has heretofore been made which attempted to deal with all facets of the problem, but in the attached review I have attempted to cover all aspects.The review mentioned by Beecher became an article, "Experimentation in Man" published in JAMA on January 31, 1959, as a Report to the AMA Council on Drugs, as adopted by the Committee on Research. In it, he stated the report's aims, reviewed the history and scope of human experimentation, gave suitable characteristics for human subjects and investigators, distinguished between permissible and nonpermissible forms of human experimentation, reviewed moral and ethical aspects of human experimentation, raised emerging legal considerations, detailed the extant "codes" available to guide the ethical conduct of human experiments, and made recommendations to investigators on the conduct of experiments in humans. [4]Widely disseminated and widely praised before and after publication as a report and as a small book, Beecher, with the benefit of hindsight, reflected on "Experimentation in Man" at a later stage in his career, saying "... it has all the impact of a feather in a high wind." It was failure to gain immediate and broad-based acceptance of his position that set up the next phase of his crusade.After "Experimentation in Man," Dr. Beecher continued to write about ethics in clinical research, particularly informed consent and the use of placebos in therapeutic comparison studies. In 1962, "Some Fallacies and Errors in the Application of the Principle of Consent in Experimentation," appeared in Clinical Pharmacology and Therapeutics. Here he enunciated the "two problems in the field of human experimentation which in any hierarchy of human experimentation are at the top level of difficulty." In the article he identified these as, first. "... the problem of consent, seemingly so simple and straightforward..." and second, "the problem of the ethical justification for experimentation on one subject which cannot in any way be construed as for his benefit but is for patients in general. [dagger]" [5]In the printed asterisk footnote to this statement, Beecher commented further on justification, stating that "Experimentation in one patient, not for his benefit but for patients in general, poses problems: Many are in the painful position of not rejecting the benefits obtained from this source but of rejecting the means which produced the benefits. To me, this is indistinguishable from the view that ends justify means." [5]By making this statement, Beecher acknowledged the intrinsic conflict in ethics that exists for the clinician who is also a researcher, a conflict that took some time to be broadly acknowledged by investigators even at such research facilities as the National Institutes of Health.Dr. Beecher further developed his ideas on consent and placebo use in "Ethics and Experimental Therapy," an editorial published in the November 30, 1963 issue of JAMA. Beecher discussed the role of sha, and placebo operations and advocated their use in surgical clinical trials. Referring to a proposed study on thymectomy, he cautioned that "Such a study could be carried out only with consent, when all patients had the situation fully explained to them and were told that they might or might not have a thymectomy, that half would be kept in ignorance of what was done until the study was completed." Citing the example of internal mammary artery ligation procedures, he maintained "It is no use to say this cannot be done," noting "... two groups have already carried out such controlled studies" and thus proved that ligation of the internal mammary arteries in management of angina pectoris resulted in "... great (and transient) improvement..." which was "... as great after the sham procedure as after ligation." He further noted that "... this useless and dangerous operation (the death rate was appreciable) was completely discredited in only 2 years after its enthusiastic introduction into this country..." as a result of the placebo-controlled surgical trial. [6]Perhaps fortified with the scientific certainty his surgical example provided and the moral authority afforded by the passage of The Declaration of Helsinki by the 18th World Medical Assembly in 1964, which addressed, in part, the subject of humans in research; Dr. Beecher moved forward with his mission to publicize abuses of researchers' discretion. He made his boldest expression of concern about consent in clinical research on March 22, 1965 during a presentation at the Brook Lodge Symposium for Science Writers, sponsored by Upjohn Company in Kalamazoo, Michigan. At Brook Lodge, Dr. Beecher presented 18 examples of clinical investigations wherein no study participant consent was obtained before patients were enrolled in experiments from which they received no direct benefit. For the first time, Henry K. Beecher spoke publicly about a subject that, here-to-fore, had been aired yet barely heeded in the medical research community.Reactions to Beecher's revelations were swift and not confined to medical participants at the conference. In a letter to George Burch, June 27, 1966, Beecher later reported, "I really was subjected to the most humiliating experience," when Dr. Thomas Chalmers and Dr. David Rutstein, both colleagues at Harvard Medical School, "called a press conference to refute what I said without finding out whether or not I could be present." The New York Times, the Wall Street Journal and regional newspapers, such as the San Jose Mercury, carried the story, evoking comments such as this unsigned letter sent by a San Jose reader directly to Dr. Beecher, dated April 5, 1965, and which is among his personal files at the Countway Library:Dear Dr. Beecher,I am sending you this artical [sic] of my paper, rather than writing you a long note.I just want you to know how much I enjoyed this artical [sic], and I know there are many, many more people who feel the same way. We need more, a lot more Doctors like you who will tell the people the honest truth. But try and find them to-day. It is realy [sic] sad.Thank you Dr. Beecher and continue to speak the truth,God Bless you always.Such acknowledgment from the lay public of his position must have energized Beecher as much as the opposition he perceived from the sophisticated medical research community. After Brook Lodge, he was galvanized into action, and in 1965 and 1966 he wrote and published with greater purpose about ethical issues, all while preparing a major article based on the materials he presented at the Brook Lodge Symposium. In "Consent in Clinical Experimentation: Myth and Reality," published in JAMA, January 3, 1966, Beecher gave a hint of how adamant he was in his views on the subject, saying "... codes dealing with human experimentation start out with the bland assumption that consent is ours for the asking." Calling this notion "a myth," he went on to assert that "... informed consent is often exceedingly difficult or impossible to obtain in any complete sense" and that "... difficulties inherent in this complex situation are no excuse for giving up the effort: informed consent is a goal toward which we strive..." [7]Two months later, in another article, "Some Guidelines for Clinical Investigation," published March 28, 1966 in JAMA, Beecher articulated his thoughts on ethical problems in research on different groups of study subjects: normal volunteers, self-experimentation, patient volunteers, patients requiring therapy, and patients who receive no benefit but whose participation benefits others. In an unusual move, considering the public circumstances, the JAMA Editor printed a disclaimer at the end of Beecher's article, saying, in effect, Beecher speaks alone:Although it is not customary to print a disclaimer with a signed communication in The Journal, the comments by Dr. Beecher have been prepared in his office with consultation as determined by him. The American Medical Association has taken no official action on this important subject. Appropriate councils and committees and the staff have this subject under study and will report at a later time. [8]In the midst of writing and publishing the aforementioned articles, Beecher worked to achieve his prime goal: to publish a comprehensive review of medical research experiments wherein investigators breached basic standards of informed consent. His original hope was to publish an article in JAMA based on 50 examples of studies like those he presented at the Brook Lodge Symposium. On August 20, 1965, Beecher submitted such a manuscript, which he entitled "Ethics and Clinical Research." In the cover letter to Dr. John H. Talbot, Editor, he asserted that his effort, to which he had "... given about ten years as careful thought as I am capable of going..." had been read by many people, "... including the president of the Medical Society by the that it should be and the the not as by his work as the to Beecher Dr. wrote on 1965, that he was the with comments from the two who reviewed it before the not to publish it as The comments noted the of for the studies mentioned and the of the article as for not publishing it in Beecher submitted his article to the New Journal of on November 10, 1965, stating in his cover letter that he had "... no to it being and published in two As in his with Dr. at JAMA, Beecher an in his letter to Dr. Editor, with greater effect. is an of the problems in this he "I believe that some exceedingly common and practices are will in the of the the that more than was to achieve he "I do believe that most people need only to be to the problems in to correct in the of his examples was no in of his with the Medical review was not the Dr. sent of Beecher's article to only one of thought the article should not be published in some editorial work In his January 4, 1966 letter to Beecher, him to the more and "... the or examples be a of be prepared in the way and of being to the of the Beecher, to submitted a with examples and on January March 3, 1966, wrote Beecher to say he had his editorial work and had the he In his letter, is the result of my editorial in which I have attempted to important to a of I have to or what we want is not an but a and presentation of what has been done and is being done in of basic my this the all the more June 1966, "Ethics and Clinical appeared as a article in the New Journal of in 1966 the had neither the nor the it has Beecher was to have his important work in and attention to he the for the of or ethical procedures, and on the problem of consent. After this he presented his examples under the following study of physiologic studies studies to the of study of and studies is no "Ethics and Clinical its about the article appeared in the the Wall Street Journal, the and other major from the medical community was Beecher wrote on June 28, 1966, that he had not received "... a letter, but many from this medical community with do not that you have received some I have been at the of the the perhaps of had received only four by August These appeared with Dr. Beecher's in the 1966 his Beecher acknowledged and explained the for what many thought was his of On this Beecher his have thought to the should have been the that these should not be of in his office and for of by the and two of his I had no to to but rather to what I to be I was by a distinguished that a of the investigators could be on by the I no in such an the Beecher had ethical high The of his article was as as he had it would of his work greater of research and gave to the that human research be by review his work of what of interest for physicians who are also clinical His participation in this illustrates how and in How this same and took the community is the of the of this Beecher faced the issue of on a patient not for his benefit but for that, at least in of patients in by fellow researchers in as as by the medical research community at is to his examples among the given in the article were from anesthesia research on in Beecher's had he the original 50 he would have more, the of examples from at about of the not identified in the article at the time, example 7, rate and during of anesthesia at normal and was by A. A. R. H. A. M. R. and H. and was published in Anesthesiology in in to during was by A. and and was published in JAMA in these two examples under in his among the Beecher files for research of Beecher's article by any of the of the two examples from with of Dr. Beecher's no of in the community to his New Journal of look at the after publication of "Ethics and Clinical however, that Beecher and Clinical however, that Beecher and a research of Long, R. and H. the of a study published in Anesthesiology in The that followed was and took in both a and public no signs of among the study in question was of of in of by Long, R. and H. study are not to this article, to say that it the of by and their with in patients with In many it to the study Beecher as example in "Ethics and who was of Anesthesiology when the study was that publication of this study was by from the regarded the study as and thought what was done to patients was He also said the he could be for he did not publish their work when he publication of the One can such a on the Anesthesiology Editorial of the is was unusual from the is that the article appeared with a in a footnote by the to the question of informed consent during the study of In it they that the problem of consent always exists in any human experiment and that, of subjects "... an informed consent cannot be obtained for a study of this of the of to a patient both the information and the to and such way of of their the we have the role of of the rights and only I is concentration must not must be and rate of administration of must be the in these the is when an was perhaps an of the to the issue of informed consent after Beecher's 1966 article that Beecher was not the first to to the researchers' published Dr. in a letter published in the issue of Anesthesiology, was the first to the In his letter he said that "... the problem of a consent for experiments on his or is not by an who the problem role of of the the of this he there is an between the to guarantee the rights and the failure to the of those the to informed consent or guarantee of this is is at is the to experiments on person, and to the information to a the information cannot be the experiment should not be carried the of his statement, Dr. perhaps without it, Dr. Beecher's position that a experiment had to be ethical from its its were to be regarded as scientifically The to Dr. letter, printed in the same was by Dr. ethics of is much he have been in this for and that we have developed a but his view that informed consent is impossible to obtain and that the be and as the for the patient during general prepared to the study by that he would one of his to the he it to be was not to the being out in On 20, he wrote Dr. stating that he had "... given a lot of thought to the Long, and in the to the Beecher to in on the but had been to do so without thinking his position through in many it would have been to have to their as as it was he "I could not do this it seemed to me to be such an important and one to be thought As a Beecher sent a of his proposed to the to Dr. for review and to his of a The of between Beecher, and illustrates the in which these of the before January Dr. wrote Dr. Beecher to say that he and his "... are not by letter to