Dear Dr. Borror: 6/5/03

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1 Dear Dr. Borror: 6/5/03 I write to request that the Director of the OHRP review the evaluation of the case that I recently brought to your attention. I refer to the case identified as: Human Research Subject Protections Under Federalwide Assurances FWA-3245 and FWA-301 Research Project: Survey of Two Homeopathic Medicine Practices BIDMC Project Number: Principal Investigator: David Eisenberg, M.D. The journal reference for this study is: Barnett EB, Levatin JL, Chapman EH, Floyd LA, Eisenberg D, Kaptchuk TJ, Klein JO. Challenges of evaluating homeopathic treatment of acute otitis media. Pediatr Infect Dis J. 2000;19: I have several concerns regarding the OHRP s determination. First, it seems that the OHRP s disagreement with several of my allegations hinges on a distinction between observational and treatment studies: OHRP finds that the research was not a treatment study but an observational study of those children whose parents had elected to pursue homeopathic care before the study was initiated and that the risks to children were no more than a minor increase over minimal risk. This is curious. 45 CFR 46 does not make this distinction in its definition of research. All of my allegations were based on regulations that refer to research as defined in (d). I can find only one passage in Part 46 that might be interpreted to exempt the research from the usual requirements of human subject protections by virtue of being observational. 45 CFR (b)(2) exempts observation of public behavior, but the behavior involved here was not public. Even if it were, a footnote to the same regulation states: The exemption at 45 CFR (b)(2), for research involving survey or interview procedures or observation of public behavior, does not apply to research with children except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed. 1

2 Since at least two of the investigators did participate in the activities being observed, there is no basis for exempting this research by virtue of it being observational. Nor was it Research involving the collection or study of existing data, an exemption that is vaguely implied by the phrase, whose parents had elected to pursue homeopathic care before the study was initiated In this case, new data were generated for the purposes of the study and reported in the paper. Thus the OHRP, I respectfully submit, is making new law if it finds that the observational nature of this study exempted it from the usual requirements of 45 CFR 46. Other recognized treatises on human subject protections make no distinctions between observational and treatment studies. The word observational is not found in the Belmont Report, which is an important historical basis for both 45 CFR 46 and the OHRP itself. The pertinent passage from the Belmont Report is this: the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects (emphasis added). The Declaration of Helsinki plainly states: In any medical study, every patient including those of a control group, if any should be assured of the best proven diagnostic and therapeutic method. The word any is unambiguous. It is the Belmont Report, incidentally, that investigators at the Beth Israel Deaconess Medical Center must agree to honor, as part of the Center s IRB Compliance Training Program. My second concern involves the statement, in your to me of 5/13/03, that the researchers needn t have disclosed alternative courses of treatment because the research did not involve any interventions. But the paper reported a total of 57 interventions in 24 children over a period of 28 days. This is clearly documented in Table 1, page 274 of the article. It is also documented several times in the text. In the Methods section is this statement: A single homeopathic medicine was prescribed for each patient, using standard, individualized homeopathic indications. These prescriptions are interventions, and their description as methods identifies them as an integral part of the research, not merely as incidental to the research. Another troubling statement in the same is this: OHRP finds that the risk of not receiving antibacterials was not a risk of the research. This is simply wrong. The risk of not receiving antibacterials was the major risk of the research, whose methods involved receiving something other than antibacterials. I must also disagree with this statement: OHRP agrees with BIDMC s determination that this research did not involve greater than minimal risk. By its definition in 45CFR (i), Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than 2

3 those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. The probability and magnitude of harm or discomfort anticipated in treating acute otitis media with something other than standard antibacterials are unequivocally greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. To deny this is to deny the cumulative AOM literature of the past 50 years. In this study ample evidence of superfluous discomfort was supplied by the paper itself, which reported many instances of new prescriptions given to children over a 28-day period far longer than the expected course of AOM treated with antibacterials. The BIDMC does not have a department of pediatrics, which calls into question the wisdom of its determining what constitutes minimal risk in research involving children. Was the OHRP aware of this fact? I believe that the foregoing are sufficient arguments for reversing the several key findings of unsubstantiated allegations in this case. Nevertheless, I am also concerned about our disagreement over the meaning of CFR (a)(2), which has more general applications. I respectfully submit that the OHRP s interpretation was, in this case, incorrect. The language of the regulation is ambiguous: In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). This could be interpreted in either of two ways: 1) that the IRB should consider only those risks additionally imposed by the research, beyond those that researchers believe would have existed without it (it is this interpretation that, based on your to me of 5/13/03, the OHRP appears to have used); or 2) that when subjects are to be recruited to join a study, the IRB should consider those risks and benefits that may result from the research (as defined by its methods ), regardless of what risks and benefits may have accrued to the subjects even if not participating in the research. Language alone favors the second interpretation. Observers can only be certain that subjects will be exposed to the risks and benefits of the research; what might have happened without it, however likely it may seem to some, can t be known. The quotation from the Belmont Report that if there is any element of research in an activity, that activity should undergo review also favors this interpretation. It is the second interpretation upon which I based my complaint. Paradoxically, for the purposes of the current study the two interpretations are almost perfect opposites; thus it is necessary to resolve the ambiguity. I will try to convince the OHRP that the second 3

4 interpretation is correct, not only by the argument in the previous paragraph, but also for the following reasons: 1. The second interpretation provides more, rather than less, protection for human subjects. More protection is the intent of Part 46, of course, and is especially important for vulnerable subjects such as the children involved in this study. In this case it would have protected the subjects from having vital health information concealed by researchers who sought parental consent. It was in the researchers interest not to explain the risks and benefits of nonstandard vs. standard treatment of acute otitis media, because to do so might have convinced parents to pursue antibacterial treatment instead of homeopathy, thus derailing the study. The Belmont Report is explicit and adamant in warning against this very problem: Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects. To show lack of respect for an autonomous agent is to repudiate that person's considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so. (Emphasis added). It goes further. It requires researchers to actively promote the well-being of subjects: Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. In this document, beneficence is understood in a stronger sense, as an obligation. (Emphasis added) Thus not only were the researchers in this study ethically obliged not to withhold discussion of the standard treatment of AOM from the consent form, they were also obliged to introduce the topic and to recommend standard treatment for AOM even if they expected the parents to refuse. That the subjects were incapable of giving their own consent and were vulnerable to coercion makes this obligation all the more important. The two treating homeopaths were also co-researchers, which suggests more bias: it is hard to imagine that they would have been pleased if the other researchers, 4

5 one of whom is a nationally recognized expert in childhood infectious diseases, had undermined their advocacy for a rarely used treatment that lacks any basis in science or preclinical studies. But that would have happened if these researchers had honestly informed the parents of the status of homeopathy, while also explaining to them that AOM is a risky disease that was a major cause of childhood morbidity in the pre-antibiotic era, but is now routinely cured by a medicine that is remarkably safe and based on the highest level of evidence. As discussed above and in my original letter to you, the homeopaths persistence in prescribing nonstandard treatments, even in the face of multiple treatment failures in 2/3 of the subjects over several weeks, confirms this bias. It is also an indictment of the other researchers, who stood silently by while this happened. 2. An illustration shows that IRBs conform to the second interpretation of (a)(2) in common circumstances. I am a member of my hospital's IRB. We frequently review protocols for chemotherapy regimens. One of the arms in such studies typically involves a regimen that is in current use and that the subjects would be likely to receive even if not in the proposed study. This fact is even stated in the consent form. Nevertheless, the consent form also describes the risks, benefits, side effects, alternatives, etc., of that regimen, and if it did not we would not approve the study. 3. OHRP language appears to require every investigator, including unaffiliated or independent investigators, to accept the responsibility to comply with the standards and requirements stipulated in various internationally recognized documents, including the Belmont Report and the Helsinki Declaration. As previously argued, there is nothing in those reports that distinguishes observational from treatment studies, but there is an obligation to fully educate subjects or subjects surrogates and to provide the best proven therapeutic method. It would be a contradiction and a detriment to human studies protections for the OHRP to countermand the expectations of these reports because of a regulatory language ambiguity. The Declaration of Helsinki agrees: No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration. Incidentally, did the homeopaths sign Unaffiliated Investigator Agreements or Agreement[s] for an Independent Investigator? If so, they were in violation of the Belmont Report, and hence those agreements, at the moment that they presented the consent form to the parents and in the 55 documented instances that they declined to prescribe proven therapy to the subjects. 4. The Tuskegee syphilis study was also an observational study. I alluded to this briefly in a previous correspondence to you, but it deserves an expanded discussion. The language of the Declaration of Helsinki and the Belmont Report was a response, in part, to the Tuskegee study. The OHRP itself is a legacy of the Tuskegee study. But if the Tuskegee study were being investigated now and if the current OHRP interpretation of CFR (a)(2) were correct, an important basis the broadest basis, I will argue for finding that the Tuskegee study was in violation of federal code would be lost. 5

6 In the absence of the study the subjects, being poor and living in the rural South, were unlikely to have had access to the best proven diagnostic and therapeutic method of the time. Many would have been unaware that they even had a disease, and many would have preferred to avoid doctors, a problem that was reported in the study itself. At least some subjects would have had little access to penicillin for the first several years after its introduction (I am aware that some would have been offered it via the military or other outreach attempts, had the researchers not thwarted those attempts). Thus in the study many, perhaps most of the subjects received the same (non) treatment that they would have received even if not participating in the research. The investigators were merely "observing" them, and the natural history of their disease, in their usual context. This was the justification offered by the researchers themselves. I attended a lecture on the Tuskegee study while in medical school in the 70s. The lecturer reported that the researchers, when finally taken to task, had argued that it was an observational study whose noble purpose was to learn about the natural history of an important infectious disease by looking at a population that would otherwise likely have remained untreated (for all the reasons given above). They hadn t considered this unethical because they hadn t exposed the subjects to any additional risks; in fact, so the rationalization went, the subjects had received better medical care, even without specific anti-syphilis treatment, than they would have had if not for the study. Granted, there are many reasons that the Tuskegee study was unethical, including the fact that it targeted an ethnic minority whose bad treatment was more likely to be tolerated by the majority at the time, and that it depended on this group s lack of sophistication, i.e., vulnerability, to permit the investigators to conceal vital information. The researchers diversion of some of the subjects when outsiders proposed effective treatments was unconscionable. The more general reason shouldn t be overlooked, however: even if the subjects had been rich white people, or even if they had constituted a perfect fractional representation of all socioeconomic subgroups in the United States at the time, and even if the researchers had not blocked treatments offered by others, the study would still have been flagrantly unethical. It was the deliberate concealing of information in order to obtain the subjects consent that made it so, and this objection would have applied even if all the others had been remedied. As quoted above, the Belmont Report plainly establishes such concealment as unethical and makes no exception for observational studies. Nevertheless it is clear that if the OHRP were to apply its current interpretation of CFR (a)(2) to the Tuskegee study it would have no choice but to conclude, as it did in the case under discussion: "The risk of not receiving antibacterials was a risk to the subjects that would exist even if the subjects were not participating in the research. Therefore, OHRP maintains that this allegation was not substantiated." 6

7 There are, of course, striking parallels to the AOM study discussed here. The subjects in both studies were members of vulnerable groups, and in both cases the investigators could not have initiated and maintained the study without nurturing their subjects (or their subjects parents ) ignorance about modern medicine... The issue of vulnerable populations raises another troubling point. There was no compelling reason to perform this study on children at all. The Belmont Report states: When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. But the only justification offered in the paper was this statement: Homeopathy is a frequently used alternative therapy for AOM. That assertion was accompanied by a reference to a survey performed by one of the authors, which reported nothing about homeopathy for either AOM or children and a very low incidence (0.33%) of adults seeking consultations with homeopaths for any reason. It was therefore a false assertion, and since its author was also the author of the cited survey it is hard to imagine that it was a mere oversight. It is reasonable to wonder if it was a deliberate deception. Nor did the authors offer any justification for studying homeopathy in humans in general, least of all for diseases that have proven therapies. The practice has no basis in science or in animal studies (even though its proponents claim that it works in animals, thus begging the question of such studies). Until it does it can t be considered ethical to submit human subjects to homeopathy trials in which proven therapies are withheld from any subgroup or, as in this case, from the entire group. In closing I pose two questions: what if one or more of the subjects had suffered a severe injury, or death, from complications of AOM? In that case it seems clear that in retrospect the lack of protections would be glaringly obvious. It is unsettling that we can t be sure that serious injuries did not occur. Nowhere in the paper or the consent form is there any mention of outcome assessments, but the presumption of treatment failures may be inferred from the report of repeated homeopathic prescriptions over a period of four weeks. Discomfort of longer than the usual duration certainly occurred. Subtle hearing loss, vestibular dysfunction, and tympanic perforations are all within the realm of clinical likelihood, and more serious complications are distinctly possible. The second question is this: what if the disease had been acute bacterial meningitis? Again, the lack of protections would seem obvious. One might argue that even homeopaths wouldn t delay rational treatment for life-threatening emergencies in children, but one would be wrong. i One might then argue that the other physicians wouldn t have tolerated this. Perhaps this is true, but if so it only bolsters the arguments presented herein: if these physicians wouldn t have tolerated withholding proven treatment for one serious but curable disease, they shouldn t have tolerated it for another. Likewise, the OHRP cannot make one finding for research involving one such disease 7

8 and the opposite finding for a similar protocol involving another. The rules are the same, and for good reasons. Again, I ask that the Director of the OHRP review the findings in this case. Sincerely yours, Kimball C. Atwood, M.D. i Lee AC, Kemper KJ. Homeopathy and naturopathy: practice characteristics and pediatric care. Arch Pediatr Adolesc Med Jan;154(1):