Mild Infections Require Placebo Controlled Trials Industry Balks

Otitis media or middle ear infection might be the clearest example. These are the typical ear infections occurring mainly in childhood starting at around 6 months of age. Otitis media is painful and for many years clinical practice in the US was to treat them with antibiotics in the belief that killing the bacteria that cause the infection would result in more rapid relief of pain and would prevent potentially serious complications. Many parents in the US have had the experience of taking their sick child to their physician or to an emergency room for these infections. Some children who had repeated episodes were even given antibiotic prescriptions in a "just in case" sort of arrangement. If they had typical symptoms, they would call their doctor and start antibiotics until they could get into the office. It goes without saying that many antibiotics have FDA approval for their use in otitis media -all based on trials comparing one antibiotic with another and none with a placebo control. For the pharmaceutical industry, otitis was a very lucrative market.

However, a number of clinical trials comparing antibiotic to placebo were carried out, mainly outside the US, which seemed unable to show a clear advantage of antibiotic therapy over a simple prescription of a pain reliever. In some of these trials, it appeared that infections caused by one particular organism, Streptococcus pneumoniae, required antibiotic therapy for cure. But this organism only caused a minority of all otitis and there is now a very effective vaccine that protects, to a certain extent, against otitis caused by S. pneumoniae. Many studies later, it seems that the best approach is one of expectant therapy. The child is given a pain-reliever. If they still have symptoms after 2-3 days, an antibiotic is prescribed. In these circumstances, around 80% will not need antibiotics. There is no difference in any outcome between patients given antibiotics immediately and those treated expectantly. The agency now requires a placebo-controlled trial to prove that an antibiotic works in otitis. Given the data, we can agree that this is a reasonable requirement.

Some pediatric infectious diseases specialists disagree that patients with true otitis media do not need antibiotics. They argue that the diagnosis in many of the placebo-controlled trials that were carried out in the past were faulty and did not represent true bacterial infection of the middle ear. They claim that antibiotics can play an important role in shortening the duration of disease and preventing complications in true otitis media. This disagreement has led to an ongoing placebo controlled trial in Finland that is being funded by Finland. The patients are very carefully examined such that the diagnosis of otitis is not in doubt. This may be the first trial where there will be no argument about whether the patients actually have otitis and where there is an untreated control group. If this trial shows a significant benefit for antibiotics, it is possible that placebo controlled trials will be a thing of the past. If there is no benefit, of course, it will mean that for most patients antibiotics are not necessary. Whether such data would alter clinical practice and patient attitudes is another question.

The American Society of Pediatrics tried to promulgate guidelines suggesting that patients with severe symptoms, those age <6 months and those where the diagnosis is certain that it is otitis media be treated with antibiotics immediately. This leaves older children, those with milder disease and those where the diagnosis is less certain (the majority of patients) available for expectant therapy. In spite of these guidelines, recent surveys have shown that only 15% of children in the US are treated expectantly. That number should be about 85%. The most common reason is parental concern (85% of parents) about not using antibiotics. In addition, physicians prefer to treat based on probability of infection as opposed to certainty. One approach some physicians have been taking is to give the parents a prescription to fill in case the expectant therapy - pain reliever - isn't enough. That way, the parent controls the destiny of their child and themselves, the doctor has provided specific therapy, and everyone is satisfied.

The major need for new antibiotics in pediatrics today might be for those children allergic to the penicillins and their relatives. Many of the pathogens that cause otitis are resistant to the other types of antibiotics approved for use in children with otitis and clinical failures do occur because of these resistant organisms. I asked a highly respected colleague working in pediatric infectious diseases how he handles this dilemma. Simple, he replied, I just use a quinolone antibiotic. He believes at least one of them is safe for use in children even though they have never been approved for treating otitis in children and other pediatricians and the FDA have expressed safety concerns about the use of quinolones in children.

Given this state of affairs, I doubt that industry will attempt to develop new antibiotics for otitis in the foreseeable future. Of course the market loss for industry is a large one. But the reduced pressure selecting for resistance by unnecessary use in otitis is a benefit for new antibiotics developed for other kinds of infections.

Sinusitis is also a large potential market for antibiotics and is more controversial. As is the case for otitis, many antibiotics are already approved by the FDA and marketed for the treatment of sinusitis based on comparative trials. According to the American College of Physicians, in most cases, antibiotics should be used only for patients with the specific findings of persistent purulent nasal discharge and facial pain or tenderness who are not improving after 7 days or those with severe symptoms regardless of duration. This recommendation is based on a number of placebo-controlled clinical trials where a modest benefit from therapy either in terms of cure or in decreasing length of illness was mostly offset by an increase in adverse effects by the antibiotics when compared to placebo. The FDA has responded to this by saying that, given the modest treatment effect, they would be unable to judge, statistically, whether a given antibiotic was inferior or not to placebo in the absence of a placebo control. However, since not treating patients with severe symptoms or symptoms lasting more than 7 days goes against medical guidance, it is difficult if not impossible to carry out the placebo controlled trials mandated by the FDA. The industry is staying away from this one. If we wanted a new antibiotic now or in the foreseeable future for the few cases of acute bacterial sinusitis that might be caused by resistant strains of bacteria, we would be disappointed. Again, like otitis, this was previously a large market segment for the pharmaceutical industry that has now virtually disappeared for new products.

Finally, there is bronchitis. This is a really controversial area. Patients with chronic lung disease, specifically, chronic obstructive pulmonary disease or COPD, have ongoing breathing problems and other symptoms like productive cough that get worse (exacerbations) from time to time. They are chronically colonized with bacteria in many cases. That is, even when they are not experiencing worsening symptoms, they have bacteria living in their lungs. Their exacerbations seem to be associated with the acquisition of new strains of bacteria in their lungs. For many years, physicians have thought that treating the bacteria isolated from the sputum (bronchial and lung secretions these patients cough up) of patients at the time of an exacerbation would shorten the duration of the episode and help avoid more serious complications like respiratory failure and pneumonia. Like otitis and sinusitis, many antibiotics marketed today are indicated for the treatment of these exacerbations all based on comparative trials without placebo controls. We now know that for so-called mild to moderate exacerbations, antibiotics appear to offer little advantage compared to no antibiotics. However, for more severely ill patients, studies suggest that antibiotics have an important role in reducing relapses, complications and in reducing mortality. According to the Cochrane Review, an analysis of many placebo-controlled trials for this disease showed a clear benefit for antibiotic treatment.

For COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill.

Again, the FDA, in spite of this sort of information, has required placebo-controlled trials for new products. Since it might not be ethical to withhold antibiotics from patients with severe exacerbations and since antibiotics might not work as well for mild disease, only one pharmaceutical company has yet ventured into this area. Their trial did show a benefit for their antibiotic, but failed to recruit a sufficient number of patients to satisfy the FDA. They went out of business shortly after their trial was stopped. (see Chapter 6 for more details). For patients and their physicians, this will mean no more new antibiotics for bronchitis. For the industry, another market has been closed. There are academic investigators attempting to conduct a placebo-controlled trial for bronchitis with funding from the NIH, but it is not clear how severely ill the patients are who are included in the trial. No data has, as far as I know, yet been published on the ongoing NIH sponsored trial.

Here are three indications where physicians perceived that there was a routine requirement for antibiotics and where that perception has been called into question. It also seems clear that, at least in some circumstances, for sinusitis and bronchitis, antibiotics are useful and in the latter case may even save lives. If we as a society agree (I do) that our current antibiotic armamentarium is sufficiently robust and that bacterial resistance is not a problem in these diseases, then I guess there is no need to further question the FDA's current stance. Unfortunately, since, in order to develop new drugs, the industry has to think 7-15 years ahead, if antibiotic resistance were to arise as a problem for, say bronchitis, we would be without important new therapeutic options for years to come.

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