2/4/03. Dear Dr. Borror,

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1 Kristina C. Borror, Ph.D. Director Division of Compliance Oversight Office for Human Research Protections 1101 Wootton Parkway, Suite 200 The Tower Building Rockville, MD /4/03 Dear Dr. Borror, I am writing to call your attention to a study in which children were exposed to serious risks in the absence of potential benefits, apparently without adequate human studies protections: 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: Summary of Study This was a pilot study of homeopathic treatments of acute otitis media (AOM) in children ranging in age from 8 months to 77 months. The authors cited no references suggesting that homeopathic treatments may be effective for AOM. Instead, they justified the study by stating that homeopathy is a frequently used alternative therapy for AOM, citing one of the co-author s telephone surveys as evidence. That survey, however, had involved only adults and reported that 1% of the 1539 adults queried, or about 15, had used homeopathy for any reason in the previous 12 months; of these about 1/3, or a total of five, had actually seen a provider. 1 The survey mentioned neither AOM nor any other disease in relation to homeopathy. Two of the co-authors of the homeopathy study, both of them homeopaths with M.D.s, treated the 24 subjects. During the course of the study they reportedly gave 23 children nothing but homeopathic medicines, i.e., placebos, for a disease for which antibiotics are the standard, proven treatment. 2 There is no mention of analgesics or antipyretics. One child received an antibiotic on day 13 at an unscheduled visit to an emergency room, another only after 28 days, presumably by the treating homeopath. There is nothing in the paper to suggest that its purpose was to study the non-antibiotic treatment of AOM, nor is there

2 any indication that the investigators performed a rational outcome assessment to assure that the children were not harmed by such non-treatment. Nor was there at the time, according to a separate article by the final author of the study, a reliable method for determining which children might be observed safely without antibiotics and which must be treated immediately. 3 I will further discuss this issue below. A table in the paper provides evidence that at least 2/3 of the children did not get better promptly. After the initial prescriptions, 8 new homeopathic medicines and 1 antibiotic were prescribed at unscheduled visits 2-13 days later; 12 new homeopathic medicines were prescribed at scheduled visits on day 14; and 9 new homeopathic medicines and 1 antibiotic were prescribed at scheduled visits on day 28. In all, 31 new medicines were given to 16 children during the four weeks subsequent to the initial visits. Each of these episodes should have been a reportable adverse event according to usual IRB criteria, 4 but only the two cases in which antibiotics were eventually given were regarded as treatment failures. Curiously, the authors seemed to acknowledge this but suggested that homeopaths are beholden to a standard of care different from the usual: In the current study failure of one homeopathic medicine to cure AOM was not viewed as a failure of therapy by the homeopathic physicians if a subsequent homeopathic medicine cured [sic] the patient. This thinking differs from the usual conceptualization of treatment failure wherein failure of the initially prescribed antimicrobial agent to cure the disease is defined as failure of therapy. Thus the rest of the authors stood by while the homeopaths mistreated children. This appears to be a violation of the Declaration of Helsinki of the World Health Organization, which states, in part: 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. 5 Nevertheless, the paper states that the study was approved by the Human Studies Committee at Boston Medical Center. The Informed Consent I wrote the Human Studies Committee at Boston Medical Center and received no reply. I subsequently wrote the first author of the study to ask about the IRB deliberations involved. She replied that, in spite of the statement in the paper, IRB approval had been granted by the human studies committee at Beth Israel Deaconess Medical Center (Boston), with Dr. David Eisenberg listed as Principal Investigator. She sent me a copy of the informed consent, which: Fails to state that the standard, proven treatment for AOM is an antibacterial agent and that there are more than minimal risks to not using one.

3 Fails to warn of the likelihood of persistent discomfort in children with AOM not treated with antibacterial agents. Fails to mention antibacterial treatment under alternative procedures. Fails to discuss compensation and medical treatments that may be available if an injury occurs. States that one of the purposes of the study is to see whether children who are treated by these doctors are less likely to have bacteria in their noses which are resistant to common antibiotics. The procedures section includes nasal swabbing for cultures. But there is no mention of this in the paper. Lists, as the only potential benefit, that cultures from the child s nose may be useful to the child s doctor. However, there is no reference to this in the paper, nor are bacterial cultures relevant to homeopathic practice. Thus the proposed benefit is not only apparently absent from the actual study, but is also misleading. Makes no mention of assent. Fails to disclose that the treating homeopaths are among the investigators. Fails to name the co-investigators. I wrote the BIDMC human studies committee requesting information about its deliberations, but after several months have received no reply. The subjects appear to have been harmed, at the least, by the unnecessary persistence of unpleasant symptoms (see below). They may also have been harmed by unrecognized, subtle hearing loss or vestibular dysfunction, particularly in the cases of the pre-verbal children. All were exposed to more serious risks. The less common sequellae of untreated acute bacterial otitis media, well known in the pre-antibiotic era, include tympanic perforation and damage to the structures of the ear with hearing loss and vestibular dysfunction, mastoiditis, facial paralysis, brain abscess, and death. 6 Meningitis is also reported to occur in association with AOM, but may not be a sequella per se. Antibiotic Resistance and AOM Recently there have been suggestions that most cases of AOM will resolve without antibacterial treatment. There is evidence that as few as 13% absolutely require such treatment, and the increasing incidence of bacterial resistance makes it desirable to treat only that cohort. The rest resolve spontaneously, although symptoms persist about 1 day longer in untreated children. 7 In the Netherlands it is standard to delay antibiotic treatment by 1-3 days and to treat only those children who remain symptomatic. 8 This has resulted in a marked reduction in the use of antibiotics in the Netherlands and in a low incidence of bacterial strains resistant to amoxacillin. The study discussed here, however, must not be confused with the effort to define rational criteria for reducing the use of antibiotics for AOM in the U.S. The reasons are as follows:

4 o This was not the stated goal of the study, nor was such a goal mentioned in the informed consent. o The first large study demonstrating the relative safety and efficacy of delayed treatment was not published until several years after the homeopathy study was conceived and performed. It was limited to children who are not very unwell systemically. 9 o Criteria for delaying treatment with antibiotics remain uncertain, and studies suggesting that antibiotics are often not required have used inconsistent definitions of AOM and widely varying antibiotic doses. 10 Thus the standard of care in the U.S. at the time of the homeopathy study was immediate antibacterial treatment for cases of AOM, with the caveat that AOM be distinguished from otitis media with effusion (OME) by the same diagnostic criteria that are reported to have been used in the study under discussion That this standard may now be in question is irrelevant to the issues presented here. o The treating homeopaths were invested in their beliefs and thus could not have been expected to resort to antibiotics in a timely fashion even if, contrary to fact, that had been the point of the study. For the investigators to have been biased in this way rendered the study unethical both because it lacked scientific validity and because it exploited its subjects. 13 That this bias was not merely hypothetical is demonstrated by the facts of the study, as follows. o In the Netherlands, the delayed treatment regimen has resulted in antibiotics being given to 31% of children with AOM; 14 in the largest clinical trial of a delayed regimen, antibiotics were given to 24% of those who deferred immediate treatment. 15 Both of these rates are far higher than the 8% who were eventually treated in the study discussed here. o Even if the two children who eventually received antibiotics represented, in the most radical non-treatment view, the 13% who truly needed them, the delay in their administration was far longer than is recommended by advocates of delayed treatment (13 and 28 days in the former cases versus 1-3 days in the latter). There was a distinct possibility of anatomical damage in these cases, but no suggestion in the paper or the IC that this was searched for or even considered. o In the Netherlands, clinical guidelines for the delayed treatment of AOM require follow-up by the treating physician within 24 hours for children under the age of 2 and within three days for older children. 16 The only stated early follow-up plan in the study discussed here were telephone calls by a research assistant on days 1, 2, and 3. The authors do not identify the research assistant as a physician. o Antibiotics begun immediately reduce the duration of symptoms and fever in AOM by about one day, even in children who would have spontaneously improved without treatment and even in children who are taking acetaminophen. 17 This underscores the fact that antibiotics are the proven treatment for AOM in general, not merely for the subset of cases that won t get better without them. The reason for limiting their use to that subset is not that antibiotics aren t beneficial for the rest, but that emerging bacterial resistance due to their widespread use may render them useless in the future. Thus clinical equipoise required the authors to make, prior to conducting the homeopathy study, a compelling case that homeopathic remedies may work as well as antibiotics not only for the sickest

5 children, but for all of them. This was not done. This requirement would have been in force even if there had been a protocol to distinguish those children who absolutely required antibiotics from the rest, which there was not. o AOM is uncomfortable. The delayed treatment regimen of the Netherlands includes acetaminophen prescribed to every child immediately. There is no mention of analgesics or antipyretics in the homeopathy paper, and homeopaths are unlikely to prescribe such medicines. The Code of Federal Regulations and the Protection of Human Subjects Apparent conflicts between this study and the Code of Federal Regulations are several: The experimental subjects were vulnerable to coercion and undue influence. 18 Assent was apparently not solicited. 19 The risks to subjects were not minimized. 20 The risks were not reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge, etc. 21 Even if the children were destined to have received the same type of treatment had they not been in the study, 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). 22 The risk was not justified by the anticipated benefit to the subjects. 23 The relation of the anticipated benefit to the risk was not nearly as favorable to the subjects as that presented by available alternative approaches, 24 i.e., antibacterial agents, analgesics and antipyretics. The risk was more than a minor increase over minimal risk. 25 The intervention was not likely to yield generalizable knowledge about the subjects disorder or condition which is of vital importance for the understanding or amelioration of the subjects disorder or condition. 26 If this was to have been merely a survey involving observations of public behavior, the investigators, i.e., the homeopaths, should not have participated in the activities being observed. 27 Were other pertinent IRBs, such as that at Boston Medical Center and that at Harvard Medical School, 28 aware of the study? Did the investigators receive investigational new drug (IND) approvals for the homeopathic medicines that they used? This would, presumably, have been required for the use of these preparations to treat AOM in a clinical study, even if they were already listed in the Homeopathic Pharmacopoeia of the United States. In summary, I believe that this study is in violation of several tenets of human studies ethics and several articles of the Code of Federal Regulations. The authors also appear to be in violation of Massachusetts General Laws governing conduct which places into question the physician s competence to practice medicine and

6 the duty of health care providers to report such conduct to the Board of Registration in Medicine. 29 I have enclosed a copy of the article and a copy of the consent form sent to me by the first author. Thank you for your consideration of this issue. Sincerely yours, Kimball C. Atwood IV, M.D. 30 Plainfield St. Waban, MA katwood@partners.org Cc: CIRCARE 1 Eisenberg DM, Kessler RC, Foster C, et al. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med Jan 28;328(4): American Academy of Pediatrics. Judicious Use of Antimicrobial Agents. In Redbook 2000: Report of the Committee on Infectious Diseases, 25 th edition. pp Klein JO. Management of Otitis Media: 2000 and Beyond. Pediatr Infect Dis J. 2000;19: Bluestone CD. Clinical course, complications and sequellae of acute otitis media. Pediatr Infect Dis J. 2000;19:S Quoted in: Angell M. The Ethics of Clinical Research in the Third World. N Engl J Med 1997 Sep 18;337(12): Bluestone CD. Clinical course, complications and sequellae of acute otitis media. Op cit. 7 Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;322: Hendley JO. Otitis media. N Engl J Med 2002;347: Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;322: Wald, E. R., Hendley, J. O. (2003). Otitis Media. N Engl J Med 348: Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Otitis media -- principles of judicious use of antimicrobial agents. Pediatrics 1998;101:Suppl: American Academy of Pediatrics. Judicious Use of Antimicrobial Agents Op cit. 13 Emanuel EJ, Wendler D, and Christine Grady. What Makes Clinical Research Ethical? JAMA. 2000;283: Hendley JO. Otitis media. Op cit. 15 Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. Op cit. 16 Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. BMJ 1997;315: Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. Op cit CODE OF FEDERAL REGULATIONS;TITLE 45; PART 46: PROTECTION OF HUMAN SUBJECTS. Revised November 13, 2001, Effective December 13, Accessed 1/03 at: (a) (a)(1) (a)(2) (a)(2) (a) (b)

7 (a) (c) (b) 28 Harvard Medical School Office for Research Subject Protection. Accessed 1/03 at: 29 M.G.L. Chapter 112, Section 5.