 Table of Contents
Executive Summary
The Otitis Media Research Center Studies
Reevaluation of the Studies
Background on Otitis Media
The Agency for Health Care Policy and Research Guidelines
The Risks to Children
International Responses to Treating Otitis Media
Acute Otitis Media in the United States
"The Cantekin Affair"
Public Policy Impact
Appendix
Executive Summary
 The federal government has just approved treatment for a common childhood illness which is not justified by the evidence, but will benefit pharmaceutical companies and will increase the risk of developing antibiotic-resistant bacteria. The research used to justify the use of antibiotic therapy to treat fluid in children's middle ears, or otitis media with effusion (OME) was funded both by pharmaceutical companies as well as by the federal government. That research had already been found by two government investigations to represent unduly drug companies' interests and to be slanted in its conclusions that antibiotics were effective in resolving OME.
The current emphasis on antibiotic therapy has an enormous impact, as otitis media (including both OME and acute otitis media -- AOM) is the most common diagnosis by physicians for children under fifteen; middle ear fluid is the principal diagnosis between 20% - 35% of the time; and according to the Centers for Disease Control antibiotics are prescribed for fluid in the middle ear 99% of the time. This case is illustrative of the growing problem caused by the general overuse of antibiotics -- the creation of so-called antibiotic-resistant "superbugs."
This report details our evidence that the conclusions drawn from the studies evaluating the efficacy of antibiotics on pediatric OME did not reflect the data. The late Rep. Ted Weiss conducted an investigation into these studies, and found that there was an "apparent bias" in the research. In 1990, as a result of the Congressional hearings, the Public Health Service performed an inquiry into the research that resulted in a five-year probation for the Primary Investigator of the research. Dr. John Bailar, the Scholar-in-Residence at the National Academy of Sciences' Institute of Medicine and editorial board member of the New England Journal of Medicine, is writing a paper in which he reports that his statistical review of the data concludes that the antibiotics were no more effective than placebos. He writes, "This remarkable trend . . . seems to demolish the conclusion that antibiotics (of the mixed types in the studies summarized in these meta-analyses) improve the outcome." In fact, the FDA has never approved the use of antibiotics for this purpose. Despite these very credible and damning condemnations of the research, parents and pediatricians have not been adequately alerted to the significant evidence that suggests against prescribing antibiotics for OME.
The Department of Health and Human Services assembled a Guideline Panel that has just issued guidelines for the treatment of OME. The prescription of antibiotics for this purpose has been approved by the Guidelines Panel, and sent to all pediatricians, HMO's and insurance companies, despite the fact they acknowledge their evidence is "limited and inconsistent". Of the eight groups of studies used by the panel to assess the efficacy of antibiotic treatment, six were based on the very study that had been discredited by the Public Health Service's Office of Scientific Integrity. However, the guidelines continue to accept the use of antibiotics as a legitimate option for treatment.
In a phone interview, Dr. Larry Culpepper, a member of the Guideline Panel, said "(T)he Guideline Panel did not find evidence supporting effectiveness of antibiotics in changing outcomes beyond one month. Not treating with antibiotics (watchful waiting) remains a very viable option."
Scholars in the field, such as the President of the American Society of Pediatric Otolaryngology, are warning of the recent emergence of antibiotic-resistant bacteria of the variety that are associated with OME -- hemophilus influenzae and streptococcal pneumonia due to the overuse of antibiotics in the treatment of OME. To make matters worse, the Centers for Disease Control has found that among children under two years old, the incidence of both OME and AOM increased 224% between 1976 and 1990.
The Otitis Media Research Center Studies
Dr. Charles Bluestone, founder and Director of the University of Pittsburgh's Otitis Media Research Center (OMRC), considered an authoritative source on the treatment of pediatric otitis media, has received more than $20 million of federal research grant money to pursue his work. Currently, nearly half of all the money the federal government spends researching otitis media in children is spent at OMRC. At the time of this research, according to a Congressional investigation and a Public Health Service review, Bluestone was also receiving $3.5 million in research funding from the pharmaceutical industry between 1980 and 1989, and did not disclose most of this private funding as the government requires. More significantly, he personally received over $262,000 in speaking fees over five years, in addition to approximately $25,000 a year in travel expenses from the drug companies that produce the antibiotics he was evaluating.(Appendix A and B)
In 1986, Bluestone sent the New England Journal of Medicine (NEJM) the results of his research on the success of Amoxicillin (a penicillin derivative), the most commonly prescribed antibiotic, in treating fluid in the middle ear, also known as otitis media with effusion (OME). He wrote in the abstract that "The results of this study lend support to the use of antimicrobial (antibiotic) treatment for infants and children with otitis media with effusion." (parenthetical phrase added) In the February 19, 1987 published version of his study, the NEJM qualified his conclusion to say, ". . . amoxicillin treatment increases to some extent the likelihood of resolution." However, this work and others from the OMRC are often cited as the source for the current frequent use of antibiotics.(Appendix C)
Reevaluation of the Studies
In 1988, the House Committee on Government Operations held hearings on the impact of mixing industry money with federal medical research. The Chairman of the subcommittee on Human Resources, the late Representative Ted Weiss (D-NY), concluded in this case that the University of Pittsburgh:
". . . also failed to examine apparent bias in the conclusions of Dr. Bluestone's published research. The NIH grantees reported that the drug was completely ineffective for treating hearing loss and that more than half the ear infections that were 'cured' at 2 weeks had recurred within 6 weeks. However, these findings were not mentioned in the conclusions of the published article or in later claims by the researchers that the drug was effective. This was a serious omission, since the recurrence of these ear infections is a major problem, and since hearing loss is the primary danger of this type of ear infection."(Appendix A)
Dr. Diana Zuckerman, a trained epidemiologist, directed Rep. Weiss' investigation and arranged for an independent statistical analysis of one of Bluestones' studies. The trial data was analyzed four different ways, and all showed that in the trial, neither Amoxicillin nor the other antibiotics were any more effective than placebos.
The controversy surrounding this research grew to the point that in 1990 the Public Health Service Office of Scientific Integrity (OSI) conducted an investigation into the allegations surrounding Bluestone's research. The report concluded:
"It seemed evident to the OSI panel that these data do not provide support for the long-term effectiveness of any of the antibiotic drugs, relative to placebos, through a period of 16 weeks (p. 16). . . . In general, the results unfortunately suggest that only a small minority will have any long-term benefits from treatment. This issue should have been given more careful attention in the treatment studies concluded at the OMRC (p. 17) . . . The later, more specific recommendations regarding each of these treatment possibilities appear to be based more upon the investigators' viewpoints rather than on data collected during the study (p. 24) . . . the panel felt that the issues raised by differing placebo cure rates and differing antibiotic efficacy rates had not been dealt with and presented as objectively as possible (p. 33) . . . the coincidence of the large pharmaceutical company honoraria to Dr. Bluestone and the less-than-objective reporting of the efficacy of pharmacological treatments present the appearance of conflict of interest." (p. 35) (Appendix D)
As a result of this report, Dr. Bluestone was placed on probation by the acting Director of the National Institutes of Health.
Currently, Dr. John Bailar, the Scholar-in-Residence at the National Academy of Sciences' Institute of Medicine and editorial board member of the New England Journal of Medicine, is completing a paper for which he performed a statistical analysis of the University of Pittsburgh research. He has concluded that the data did not support the assertion that antibiotics were any more effective than placebo in treating otitis media with effusion. Dr. Bailar wrote, "This remarkable trend . . . seems to demolish the conclusion that antibiotics (of the mixed types in the studies summarized in these meta-analyses) improve the outcome."
Background on Otitis Media
Perhaps the most common affliction children face is "otitis media," commonly referred to as ear infections. There are two types: acute otitis media (AOM) occurs when the patient experiences pain and the ear drum is red; and otitis media with effusion (OME) occurs when there is fluid in the middle ear, which may involve hearing loss, fullness of the ear, discomfort, loss of balance, or no symptoms at all. Estimates of the percentage of appointments with doctors for earaches that result in a diagnosis of OME range from 20% - 35%. According to the Centers for Disease Control, in 1991, doctors prescribed or gave antibiotics 99% of the times they diagnosed a patient with OME. [ While this statistic is technically accurate, it is based on the International Classification of Diseases (ICD). It is believed that some doctors may mistakenly use the ICD code for OME when classifying a patient with AOM.]
In 1990, according to the Center for Disease Control, AOM and OME were the primary reason for 19.7 million appointments with doctors for children under 15 years old, and 24.5 million visits for patients of all ages. As a result of those appointments, drugs were prescribed or ordered 29 million times. In 1990, Amoxicillin was prescribed ten million times or 34% of the times drugs were prescribed for AOM and OME.6
According to the American Society for Microbiology, 42% of all antibiotics prescribed to children are to those diagnosed with AOM and OME.
There has been a significant increase in the number of incidents of AOM and OME between 1975 and 1990. For those children under two years old, frequency of doctor's visits due to AOM and OME has increased 224%; for children between two and five, it has increased 130%; and for children between six and ten years old, 78.5%. (There is a common argument made in the otolaryngology community that the increase in the number of children going to day care accounts for this increase. It would seem, however, that this dramatic jump would apply more to the two-to-five age group, rather than to the children under two, who are less likely to be in a day care center.)7
Treatment for both AOM and OME is typically a steady stream of antibiotics. Usually a child will begin on Amoxicillin, and advance to the more expensive "boutique" antibiotics, including Ceclor, Suprax and Augmentin. Amoxicillin has been on the market for approximately 20 years and is now available as a generic. The total annual medical treatment (not including surgical treatment) for AOM and OME has been estimated to be approximately two billion dollars. (Berman, Roark and Luckey, Pediatrics, 1994) Dr. Stuart Levy, Professor at Tufts University School of Medicine, wrote in his 1992 book, The Antibiotic Paradox:
"More and more parents of young children suffering from ear infections are finding that the prior successes of the penicillin drugs in treating this illness may not be repeated. They must now rely on other more costly drugs to which they may have a toxic reaction." (p. 205)
The Agency for Health Care Policy and Research Guidelines
Despite the abundance of evidence, reliance on a constant flow of antibiotics to children with OME continues to be the current practice in the United States. To make matters worse, an arm of the Department of Health and Human Services just released the report of their Guidelines Panel supporting the use of antibiotics for OME, despite the fact that, in their own words, their evidence is "limited and inconsistent." The evidence they used to support this conclusion had already been found by two government investigations to unduly represent drug companies' interests and not balanced in its conclusions that antibiotics were effective in resolving OME.
The Health and Human Services Agency for Health Care Policy and Research (AHCPR) assembled an Otitis Media Guideline Panel, which determined recommendations to be sent to all pediatricians in the country regarding the appropriate treatment of OME. The Panel was co-chaired by Dr. Sylvan Stool, of the University of Pittsburgh's OMRC (and co-author with Bluestone of the textbook, Pediatric Otolaryngology). When the AHCPR became aware of the appearance of conflict-of-interest, they took several steps to try to distance the panel members who were associated with the OMRC from the discussions on the use of antibiotics. The report is a presentation and comparison of four options for the treatment of OME -- observation, antibiotic therapy, antibiotics and steroids, and surgical intervention. The research used to support the option of antibiotic therapy was based in large part on the discredited work from the OMRC.
Since the Project on Government Oversight circulated the October 1993 "Parent Guide" draft version of this report, the Agency for Health Care Policy contacted us and acknowledged that their language supports the option of antibiotics, although their data for this is "limited and inconsistent." While they subsequently reworked their description of the benefits and harms of antibiotics, they remain firm in giving legitimacy to the use of antibiotics for OME.
In the draft, the option of "observation" is described as follows: "in about 60% of children, otitis media with effusion goes away without treatment within 3 months." In comparison, they assert that antibiotics "may increase chance and speed of otitis media with effusion going away" and "may decrease chance of a future attack of acute otitis media." Based on this information, what parent would choose not to give their child antibiotics?8
In the final version of the "Parent Guide," the option of "observation" is described as follows: "in about 60% of children, middle ear fluid goes away without treatment within 3 months; in 85 percent it goes away within 6 months." In comparison, they assert that antibiotics "may increase chance (by about 14 percent) and speed of middle ear fluid going away" and "may decrease chance of middle ear infection." While this final version gives the parent more information, it clearly remains supportive of antibiotic treatment.9
The Guideline Panel acknowledged that the evidence on which they based this position came from research conducted by Bluestone at OMRC, and they felt it was necessary to describe this data as "limited and inconsistent", and that they "failed to find compelling evidence for or against" this treatment. These caveats are not included in the Parent Guide, or the Quick Reference Guide for Clinicians, but are buried in their longer Clinical Practice Guideline. Table 5 of the Clinical Practice Guideline reveals that of the eight meta-analyses (groups of studies) used by the panel to assess the efficacy of antibiotic treatment, six relied on the very study that had been discredited by the Public Health Service's Office of Scientific Integrity.10
The October draft was used as a reference for an American Academy of Family Physicians (AAFP) pamphlet on earaches. The AAFP pamphlet does not even suggest, let alone encourage, the option of "observation" or "watchful waiting" as a method of treating fluid in the middle ear. This brochure has just been sent out to family physicians around the country to give to parents who want to learn more about their children's "earaches." At the end of the brochure, the reader is directed to contact AHCPR for a copy of the guidelines for more information.11
In a phone interview, Dr. Larry Culpepper, a member of the Guideline Panel, agreed that a concerted effort is needed to educate the public. He said, "The Guideline Panel did not find evidence supporting effectiveness of antibiotics in changing outcomes beyond one month. Not treating with antibiotics (watchful waiting) remains a very viable option." The Guidelines report did not take this position on the effectiveness of antibiotics.
These Guidelines are the basis upon which all pediatricians treat their patients for otitis media with effusion, and are used by HMO's and insurance companies for their definitions of appropriate treatment.
The Risks to Children
Dr. Robert Ruben, President of the American Society of Pediatric Otolaryngology, believes that there is virtually nothing to gain from prescribing antibiotics for OME. Furthermore, he stated that the excessive use of antibiotics is creating a significant medical phenomena -- antibiotic resistant bacteria. Dr. Ruben wrote in a 1993 paper:
"Both of the most common of the bacteria associated with OME, hemophilus influenzae and streptococcal pneumonia, have acquired significant antibiotic resistance. . . . It would appear that the wide spread use of antibiotics for OME has added to the creation of antibiotic resistant organisms throughout the world. Development of these resistant organisms is increased when the antibiotic is given over a prolonged period of time. . . The creation of antibiotic resistant organisms is now a medical social problem that needs to be addressed and regulated."12
Dr. Ruben delivered a paper in May of this year in which he concludes:
"Overall, the effectiveness of antibiotics for all of the types of morbidities associated with OME is marginal or to equal that of placebo. The sequelae resultant from the use of antibiotics is substantial both to the patient and to society. Analysis of the data indicates that antibiotics are an ineffective and a dangerous form of care for OME." ("Effectiveness and Sequelae of Interventions for Otitis Media with Effusion," Ruben, May 16, 1994)
There has been additional research completed in the United States that suggests that the younger population is becoming more and more immune to the effects of antibiotics because of the overuse of this medical treatment. The result is that children are contracting illnesses that would normally be cured through the administration of an antibiotic. Because these children have already ingested significant amounts of a number of antibiotics, they have developed a resistance to these drugs, and do not respond to antibiotic treatment. In The Antibiotic Paradox, Dr. Levy wrote:
"Another now common community resistance problem has developed with Hemophilus influenzae, the cause of ear infections in infants. . . . The first appearance of ampicillin-resistant strains was totally unexpected (ampicillin is the first generation of amoxicillin). They were discovered in the early 1970s when two infants in Bethesda, Maryland failed to respond to ampicillin. They both died before the problem of resistance was diagnosed. The event sparked international concern. . . . Today, less than twenty years later, ampicillin-resistant and multiresistant Hemophilus influenzae is a problem throughout the world." (pp. 133-134)
A 1992 study of patients in Buffalo, New York researched antibiotic resistance in children previously treated with ampicillin. They discovered that 46% of children with hemophilus influenzae bacteria in their middle ear had become immune to ampicillin, and 100% with M catarrhalis bacteria were immune. (Faden et al, Ann Otol Rhinol Laryngol, 1992)
|
|
