The paper to which this is an epilogue was first written June 17 and last revised July 9, 2001.

It never dawned on me at the time that the concerns and predictions it contained would be born out so quickly.

1. I wrote that “It may turn out that we have not yet earned the right to cast moral aspersions on those who have gone 60 years before us, even in this Phase IV period of heightened awareness.”

There was then a reference to the DHHS report, “Protecting Human Research Subjects,” that noted “’disturbing inadequacies in IRB oversight of clinical trials,’ up to and including ‘the death of a teenager participating in a gene transfer clinical trial funded by NIH.’”

The notes to my main paper cite the fact that, “Since the fall of 1998 the National Institutes of Health (NIH) have shut down research programs at eight institutions, including Duke University Medical Center, the University of Illinois at Chicago, and Virginia Commonwealth University.”

I spoke of the March 2000 report of a Johns Hopkins study in Uganda that led to the unnecessary infection of 90 subjects with AIDS.

Little did I know that less than two weeks later, during the week of July 17, 2001, we would be reading news reports that the federal Office for Human Research Protections had shut down human subjects research at Johns Hopkins. (All Hopkins medical institutions received $419 million in research funds from the NIH alone last year, the most of any such institution.) The cited reason? “This is about protecting people’s lives.” The precipitating cause? The death of yet another human subject.

2. I wrote of the university administrator at the institution for which the supervisor of the 1939 study had worked:

“[He has] built [himself] a very high pulpit from which to cast moral judgments on [his] predecessors below. Unfortunately, it sits atop a shaky scaffolding from which a fall from grace could be painful. At a minimum, [he is] inviting exceedingly close examination of [his] own future actions . . .. [Is he] aware how soon it may be coming?”

Less than one week after the Johns Hopkins revelations the statewide Sunday paper in his state headlined on page one: “[his university] Faces Probe Over Research.” The story noted that, among other things,  “the issues raised . . . focus on internal review boards that sometimes rushed approval of changes in experiment guidelines and did not document procedures in enough detail.”

A letter to the university in 1999 from the Food and Drug Administration referred to its reviews at the university in 1992, 1995 and 1998. Each of those reviews involved violations that “are of particular importance because many of them have been observed during past inspections where corrections were promised by your institution but not implemented.”

According to the news story, an FDA spokesperson said it is “fairly rare to see issues remain unresolved after several visits, as inspectors suggested was the case at the [university in question].”

A spokesperson for the university tried to minimize, even trivialize, the violations as “minor administrative details.” Said another, “the more complex the research the greater the likelihood there are some failures because we are, after all, all human.”

Apparently the educational administrative standard is to be that we will be human and forgiving of our own errors, but morally outraged by those of our predecessors.

3. I wrote of the journalist who did the original stories about the 1939 study,

“The author of the stories in question was quick to formulate and cast moral opprobrium on the researcher and supervisor [of the 1939 study]. He was considerably slower in coming to an examination of his own ethical lapses. In fact, it appears he never bothered to consider them at all.”

“Journalists should . . . Avoid undercover or other surreptitious methods of gathering information except when traditional open methods will not yield information vital to the public. Use of such methods should be explained as part of the story.”

On July 25, 2001, the journalist’s executive editor felt obliged to run an editorial revealing that the journalist had violated the paper’s own ethical standards (a provision equivalent to that quoted above). He had gained entry to a State of Iowa archive that is closed to journalists by representing that his role was that of an academic researcher. The editor failed to mention any of the other ethical violations discussed in the main paper, including the violation of the privacy rights of the subjects – the protection of which was one of the purposes of excluding journalists from the archives.

4. In the course of evaluating the ethical charges leveled at the 1939 study I noted,

“To the extent any subject suffered permanent harm following the experiment it is not clear how much, if any, of that harm can be traced in a causal way to the study.”

“We have examined the data carefully and found that the study completely failed to demonstrate any support for its conclusions that stuttering could be elicited via labeling.” (emphasis in original)

"It appears to us that many active scientists in the field would be skeptical about the conclusion that a few sessions . . . would have created chronic stutterers . . .. [W]e are of the opinion that [the newspaper's] conclusions are grossly erroneous by failing to separate opinions from serious data-based assessments of the [researcher's] study."

In May 2002 a very detailed analysis of the 1939 study was published. It documented the same conclusions: the study could not have caused stuttering, and was for this, and other reasons, innocent of most of the ethical charges leveled at it. The article is appended, via link, to this one: Nicoline Grinager Ambrose and Ehud Yairi, "The Tudor Study: Data and Ethics," American Speech-Language Pathology, vol. 11, 190-203, May 2002.

The 2001 Johns Hopkins Study – and Death

In discussing the 1963 study in which patients were deliberately injected with cancer I noted that,

“Such professional concern as did exist focused not so much on the ethics of the project as on the possible adverse impact of public knowledge on . . . continued funding of such research . . ..”

There was an expression of considerable outrage by Johns Hopkins' doctors over the government’s closing down of their research (“unwarranted, unnecessary, paralyzing and precipitous”). There was after all, they pointed out, only one dead subject. You would think it was they who were the victims rather than their dead human subject and her family members.

Nor was concern about loss of funding limited to Hopkins.

The university at which the 1939 study was conducted contributed to a local news story headlined, “[local university's] Funding Unaffected by Halt in Johns Hopkins Cancer Study.” Apparently Hopkins, rather than the government, pays the university $700,000 a year for one study and $11,000 for the other. Local citizens were no doubt reassured to learn that the local research “likely will not be affected.” There was no mention of the death.

In comparing the media and institutional response between that accorded the 1939 study and the Johns Hopkins death the word “hypocrisy” may be misplaced, but “disparity” certainly is not.

There were no editorials passing moral judgment on the Hopkins researchers and their institution. No characterization of their work as a “monster study.” No calls for punishment, or for removing names from buildings. Indeed, there was not even an editorial demand for apologies to the family members of the dead subject, let alone proposals that they be paid damages – all of which were apparently thought appropriate for the 1939 study. I do not even recall any mention of expressions of sympathy or sorrow for the deceased’s survivors – though surely there must have been.

Let’s compare the 1939 and 2001 studies.

• The 1939 study was conducted before any ethical standards were in place; before even the Nuremberg and Helsinki statements. All approvals were obtained. No standards were violated. The 2001 study was conducted after decades of evolution of written and detailed standards and the existence of institutional review boards – the relevant board having approved the study. Standards were violated.

• The 1939 study involved a young master’s degree student with little or no funding. The Johns Hopkins study involved the largest medical research institution in the country; the recipient of $419 million for taxpayer-supported research.

• The 1939 study was conducted before there was any way of knowing what impact it would have upon the subjects, and every reason to believe the effect, if any, easily could be reversed. It was original research; by definition there was no prior literature. The Hopkins study involved the use of hexamethonium, a chemical about which a great deal was known and published in the literature. It was known to cause lung damage; indeed, that was the point of using it. It was given in amounts some doctors characterized as “extraordinarily large”; amounts the FDA would not have approved had they been asked.

• The 1939 study involved the maximum informed consent possible under the circumstances (that of the adult administrator of the institution where the subjects lived). No objections were raised to the study from any quarter – not the university, not the institution, and not the state agency with oversight responsibility for the institution. The least that can be said is that the researcher complied fully with all the informed consent required by any ethical standards at the time.  The 2001 study’s subjects provided a measure of consent, but it was not fully informed, as required. They were unaware of the full extent of the risks to which they were being subjected – such as death from the total destruction of their lungs. What they were told was a “medication” was in fact a lung irritant, not an asthma remedy. It was a chemical that lost FDA approval for its original intended purpose in 1972, was not approved by the FDA for this study, was being used experimentally, and at no time in its history had ever been approved in an inhaled form.

• The 1939 study is criticized because what was done to the subjects (speaking to them in ways millions of parents still do every day) did not involve the evaluation of a cure, something that could potentially benefit the subjects (whether or not they already stuttered). It was, rather, a practice that might create the condition called stuttering. But that is precisely what the 2001 study did. In researching asthma the Hopkins researchers deliberately used a chemical they knew would worsen the subjects’ lung condition. It was in no sense a "cure for asthma."

• The 1939 study is criticized because it resulted in permanent harm: stuttering. As I suggested in the original piece, and is supported by the ASHA article, above, there is considerable question about that assertion. But assume for the sake of argument the study did cause stuttering. The 2001 study caused a death. Shouldn’t death be considered a kind of permanent harm that ranks right up there alongside stuttering? Apparently not in the minds of many journalists and editorial writers.

• The very least that can be said is that the 1939 researcher did not knowingly and deliberately do permanent harm to the subjects. The 2001 researcher either knew, or ought to have known (based on the required literature search), that his deliberate actions risked permanent harm, including death, to his subjects. Indeed, his own description of the study said that its purpose “is to find out how the tubes that carry air into the lungs can stay open even when we breathe all types of irritating chemicals.” This was, by any definition, knowingly and deliberately doing harm.

• Why does a current death of a human subject at the nation’s largest, and most heavily funded, medical research institution get, in baseball’s vernacular, “a base on balls” from the media?

• Why, by contrast, does a 63-year-old study by a master’s degree student – one that may or may not have caused stuttering in a couple of subjects – get characterized as the “monster study,” given national sensationalist media play, and receive moral castigation from editorial writers?

Indeed, the Baltimore Sun’s extensive coverage of the Hopkins story (and relative lack of coverage of the 1939 study story) was commendable. It included an upbeat profile of the researcher, an explanation of the need for oversight and the harm that can come from governmental over-reaction, an exploration of the most appropriate public relations reaction for an institution in this position, and some of the conflict of interest issues that arise when the academy gets in bed with business. In short, it put the story in context. It used the story to explore some of the broader issues to its readers. It used its editorial page responsibly. (Citations to many of these stories are provided in the Notes, below.)

It’s the disparity between the coverage of the two stories that’s troublesome.

The supervisor of that 1939 study is incapable of self-defense. He’s been dead for 36 years. I would hope that the journalists and editors who participated in the assault on his good name and reputation would reflect upon some of the questions, above. But I won’t be shocked if they don’t.

It is equally interesting to note the disparity in the response of spokespersons for the university in question regarding the news coverage of the 1939 study and the 2001 investigation of current practices.

The university administrator who responded to the newspaper attack on the 1939 study said the study was “more than unfortunate” and could not “be considered defensible in any era.” This same administrator even went so far as to repeat the “unfortunate and indefensible” charge in his comments on the story criticizing the ethics of the reporter who wrote the original two-part attack!

Compare, by contrast, how quickly he springs to a defense of the institution and its medical and other researchers when government concerns about its current practices are exposed. A local paper reported “The university calls into question both the headline and its placement as Sunday’s leading story” – while acknowledging that the story itself was “mostly accurate if read in its entirety.” The headline and the story's placement? Is this an academic or a publicist who's speaking?

There was, of course, no reference to how “unfortunate and indefensible” it is that today’s clear governmental standards have not been complied with by his university in spite of repeated investigations and assurances of correction.

It’s been quite a month.

This seems to be the story that won’t quit – much as I, and I suspect many others, may wish that it would.

Seldom in life is there such an immediate need for an epilogue to one’s writing.

I hope there will be no occasions for more.

As it quickly turned out, my "hope there will be no occasions for more" was to be dashed no more than one day after the Epilogue was posted.

The AP carried the story that the journalist who wrote the original series, whose very own ethical violations were reported earlier in critical fashion by his editor, had "resigned" from the paper that published them.

Aside from that, my hope continues that this will, at last, be the end of the matter.

The most detailed reporting about the Johns Hopkins controversy has been, not surprisingly, in the Baltimore Sun. A relatively complete list is available below. See also, Gina Kolata, “U.S. Suspends Human Research at Johns Hopkins After a Death,” The New York Times, July 20, 2001.

Regarding institutional response the Sun noted, "In Rochester in 1996 [following the death of a human subject], doctors disclosed as many details as they could, at the risk of embarrassing themselves and complicating their legal position. . . . In Baltimore in the past few weeks, Hopkins leaders initially chose to reveal little, at the risk of appearing to have something to hide." Eric Siegel and Diana K. Sugg, "Management of Crisis Key to Public Trust," The Baltiimore Sun, June 24, 2001.

The comments from the university at which the 1939 study was done are found in Jim Jacobson, “UI Funding Unaffected by Halt in Johns Hopkins Cancer Study,” Iowa City Gazette, July 21, 2001, p. 1.

Some of the July 2001 stories concerning the university at which the 1939 study was done would include Colleen Krantz, “U of I Faces Probe Over Research,” Des Moines Sunday Register, July 22, 2001, p. 1; George Pappas, “Gov’t Probe of UI Research ‘Minor,’” The Daily Iowan, July 23, 2001, p. 1; George Pappas, “UI Fires Back at Register’s Headline,” The Daily Iowan, July 24, 2001, p. 1; Ryan Foley, “’Monster Study’ Reporter Under Fire,” The Daily Iowan, July 26, 2001, p. 1.

That university's continuing tenacious campaign against the Des Moines Register's headline and placement was represented in a letter to the editor with, presumably, a headline finally thought acceptable, David Skorton, "No Action Pending Regarding U of I Research," Opinion, Des Moines Register, August 5, 2001, p. 9A. The contrast between this protest -- of a story it concedes was "balanced and mostly accurate" -- and its response to the media's broadside attacks on the 1939 study are striking. In the latter case it not only failed to protest anything about the stories -- content or headlines and placement -- it actually joined in the moral castigation of its own faculty member.

A story involving that university's handling of donors to its foundation, though unrelated to human subject research as such, is equally illustrative of modern day intitutional ethics generally, their relationship to money, and administrators' reactions to the embarrassment of the media spotlight. Frank Santiago, "U of I Foundation Drops Farm-Sale Plan," Des Moines Register, August 12, 2001, p. A1.

According to the story a first-time donor presented the foundation 400 acres of farm land with the stipulation that it not be sold for 10 years, in order that the present tenants could continue to farm until their retirement. With the use of the foundation's lawyers a legal loophole was found whereby the university could accept the land, break the condition, and immediately sell it -- a strategy the family characterized as "really cheap and rotten." The foundation's legal resources were so overwhelming the family felt it was futile to fight for the donor's wishes.

From all reports the university probably would have proceeded with its heavy-handed approach if the transaction could have been kept secret. Once reported by the state-wide newspaper, however, it reversed its decision and agreed to abide by the donor's wishes.

(For the sake of thoroughness it should be noted that two subsequent stories indicate the university may have later decided to bulldoze ahead and sell the land in spite of the bad publicity and ill will its heavy-handed decision is creating among present and future potential donors. Nicole Schuppert, "UI Foundation Still Planning to Sell Land," Iowa City Gazette, August 13, 2001, p. 3B; Heather Woodward, "Donors React to UI Land Sale," Iowa City Press-Citizen, August 14, 2001, p. 3A.)
 

I wrote in the initial paper that there are a number of current ethical issues in human subjects research that really are deserving of public education by journalists. Among them is one cited by the April 2000 report of the DHHS Office of Inspector General, “Protecting Human Research Subjects.” Among a great many "disturbing inadequacies" it notes that “The increased commercialization of research and the growing importance of research revenues for institutions heightens the potential for conflicts of interest in clinical research.”

On August 5, 2001, the Washington Post reported that overreaching by pharmaceutical companies had become so bad that "editors at the world's most prominent medical journals, alarmed that drug companies are exercising too much control over research results, have agreed to adopt a uniform policy that reserves the right to refuse to publish drug company-sponsored studies . . .." Susan Okie, "A Stand for Scientific Independence: Medical Journals Aim to Curtail Drug Companies' Influence," Washington Post, August 5, 2001, p. A1. (The story was carried in the city of the university at which the 1939 study was conducted as, "Journals Adopt New Policy: Editors Aim to Clip Drug Companies' Influence," Iowa City Press-Citizen, August 5, 2001, p. 1A, and "Medical Journals Battle Drug Firms' Grip on Research," Iowa City Gazette, August 5, 2001, p. 3A.)

The author quotes "several observers of biomedical studies who have become alarmed about the influence of the drug industry on the integrity of medical research." A University of California professor of clinical pharmacy is quoting as saying that if negative results are published "you can still get pressure put on you for fear that you won't get any future funding." Companies not only control access to data, but may even control who writes the papers -- or ghost write them for the academics who "are too busy to take all the time needed to create the publication." She cites examples in which reports of side effects, no benefits, or cheaper alternatives have led to blocked publication or even lawsuits.

One would think the significance of these ethical issues for public health would be worthy of far more media attention than a 1939 master's thesis.

The newspaper in which the original series attacking the 1939 study appeared has now admitted the ethical violations by the reporter who wrote it. David Yarnold, “Setting the Record Straight,” The San Jose Mercury News, July 25, 2001. Its ethics policy, violated by the journalist, provides:

"Under ordinary circumstances, reporters or photographers ought to identify themselves to news sources. There might be times, however, when circumstances will dictate not identifying ourselves. Only the Executive Editor or Editor may approve such exceptions."

The story reporting the resignation of the journalist who wrote the original series was carried by the AP. Stories that appeared in local papers of the university where the 1939 study was done included: "Stutter Story Reporter Quits," Iowa City Press-Citizen, July 31, 2001, p. 1, and "Author of Stuttering Series Quits Paper; Reporter Criticized for Research Method," Iowa City Gazette, August 1, 2001, p. 8A.

The articles in the ASHA publication are Ehud Yairi and Nicoline Ambrose, "The Tudor Experiment and [the study's supervisor]: Science and Ethics Reexamined," and Mary M. Annett, "Article Alleges 1939 Study Taught Children to Stutter," the ASHA leader, vol. 6, no. 13, July 24, 2001.

The Baltimore Sun Stories

Jonathan Bor and Tom Pelton, “Hopkins Study Was Exempt from FDA; Asthma Project Tested Function of Lungs, Wasn’t a Drug Trial,” The Baltimore Sun, June 22, 2001.

Jonathan Bor, “Hopkins Panel to Study Death of Volunteer,” The Baltimore Sun, June 23, 2001.

Eric Siegel and Diana K. Sugg, “Management of Crisis Key to Public Trust,” The Baltimore Sun, June 24, 2001.

Douglas M. Birch and Gary Cohn, “The Changing Creed of Hopkins Science; What Once Was Heresy is Now the Mission: A Partnership with Business to Advance Research,” The Baltimore Sun, June 25, 2001.

Editorial, “Death at Research Center; Hopkins Study: Volunteer’s Death Raises Questions About Protection, Role of Human Research Subjects,” The Baltimore Sun, July 1, 2001.

Editorial, “Of Profits and Patients; Medical Research: Academic Institutions Face Huge Conflicts of Interest as They Pursue Business Ties,” The Baltimore Sun, July 2, 2001.

Tom Pelton, “Asthma Study Violated Safety Rules, FDA Says; Hopkins Experiment Ended with Death of Volunteer, 24,” The Baltimore Sun, July 3, 2001.

Tom Pelton, “Respected Doctors Confront a Tragedy; Experiment: With a Research Subject’s Death, Two Distinguished Scientists Confront What Colleagues Say is the Worst Imaginable Outcome,” The Baltimore Sun, July 8, 2001.

Editorial, “An Unnecessary Death; Hopkins Study: Tighter Controls on Human Research Projects Needed; Institution’s Inquiry Finds Faults,” The Baltimore Sun, July 18, 2001.

Jonathan Bor and Tom Pelton, “U.S. Halts Hopkins Research; Most Experiments on Human Subjects Ordered Suspended; Federal Funding Withheld; Oversight Agency Decries Safety Lapses in Volunteer’s Death,” The Baltimore Sun, July 20, 2001.

Michael Stroh, “Shutdowns Have Wide Effect on Programs; Cutting-edge Treatments Become Unavailable; Funding, Name Damaged,” The Baltimore Sun, July 20, 2001.

“Hopkins Calls Federal Agency’s Action ‘Precipitous,’” The Baltimore Sun, July 20, 2001.

Editorial, “Protecting Humans in Research; Hopkins Shutdown: Government is Right to be Concerned, but Wrong to Punish Researchers so Harshly,” The Baltimore Sun, July 21, 2001.

Diana K. Sugg, “Despite Suspension, Hopkins Researchers Continue Vital Tests; Doctors, Nurses Rush to Reassure Patients, Appeal Research Bans,” The Baltimore Sun, July 21, 2001.

Tom Pelton and Jonathan Bor, “Hopkins Vows to Improve Research Safety; Changes Outlined in Letter School Sent to Federal Agency; ‘It’s Been Utter Confusion;’ Lifting of Suspension Sought by Next Week,” The Baltimore Sun, July 21, 2001.

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