Pneumonia The New Frontier New Trial Requirements for Pneumonia Will Make Approval Much More Difficult and Costly and Sometimes Simply Infeasible

Along the same lines as their inquiry on otitis, sinusitis and bronchitis, the FDA recently examined the role of antibiotics in pneumonia. Those of us in the infectious diseases community held our collective breath waiting to see if the FDA would decide that they did not understand whether antibiotics had an effect on bacterial pneumonia. To us clinicians, that antibiotics have a dramatic beneficial effect in the treatment of pneumonia was obvious and well proven by our own personal experiences as physicians and by clear historical precedent. Many of us could not understand what the FDA was thinking.

Pneumonia is generally divided into two categories - infections acquired in the community and those acquired while in the hospital. Both can be lethal. Community-acquired pneumonia strikes four to six million Americans every year. 600,000 are hospitalized and tens of thousands die leading to an annual cost to the US of over $10 billion.

In order to begin to understand the importance of antibiotics in the treatment of pneumonia, we have to delve back into history. When antibiotics were first developed in the 1930s (sulfa drugs) and the 1940s (penicillin), clinical trials as we know them today were not performed. Physicians would treat patients with the antibiotic and then search among hospital records for other, similar patients who were not treated (historical controls) or they would compare treated patients to similar patients in the hospital at the same time but who were not treated (concurrent controls). Obviously, this is not the same as asking a patient to agree to be either treated or not in a blinded fashion such that neither the patients nor the treating physicians know who is on which therapy as we would do in a contemporary trial. Nevertheless, when we look at deaths from pneumonia in these older studies, antibiotics prevented anywhere from 16 to 26% of them.

This analysis is not as straightforward as we would like. Community-acquired pneumonia has a variety of causes and not all of them are treated well with penicillin or sulfonamides, the antibiotics studied in the 1930s and 1940s. Some cases are actually due to viruses that are not treated by antibiotics at all. Even so, antibiotics still prevented 16% of deaths in all comers in those early studies. Table 4.1 below has been modified from the position paper presented by the Infectious Diseases Society of America to the FDA in 2008.

Table 4.1 Historical Studies of Antibiotics (penicillin or sulfonamides) in Patients with Pneumonia

Untreated mortality

Treated mortality

Historical-control Studies

2184/5747 (38%)

398/3293 (12%)

Concurrent-control Studies

58/254 (23%)

21/308 (7%)

In other studies, if we look at only those patients who were infected with the most common bacterial cause of pneumonia, Streptococcus pneumoniae, and among those we look only at those patients that had invasion of the bloodstream by the bacteria (10-20% of patients), penicillin or sulfonamide prevented anywhere from 30 to 80% of deaths. If we don't look at deaths, since very few patients die from pneumonia today (because we have such good antibiotics in large part), but we rather look at time to normalization of temperature, we get a different perspective. In one study of sulfonamides from the 1930s, 84% of antibiotic treated patients were afebrile by 72 h compared to 2-3% of untreated patients. Clearly, antibiotics work and they work well. The overall mortality for pneumonia today, taking all comers in clinical trials, is around 3%. Any physician who has treated a patient with bacterial pneumonia can testify to the dramatic effect of antibiotics in this disease (see Chapter 2).

Do we need new antibiotics for community-acquired pneumonia? Probably not today. Our antibiotic armamentarium is diverse enough given the emergence of resistance that we are seeing that, in my own view, there is not an urgent need today for new antibiotics to treat this disease. The problem is that we have to think 7-15 years into the future. The risk is unpredictable. Who would have predicted the epidemic of vancomycin-resistant enterococci that has devastated our intensive care units since 1989? My crystal ball is telling me that in 10 years, having a new antibiotic for this disease would be worthwhile, especially for those patients allergic to the penicillin type drugs, given today's rate emergence of resistance to the non-penicillin type antibiotics. Of course, today if you are one of those rare individuals who can take neither the penicillins nor the quinolone antibiotics, you still have Ketek, which remains approved for pneumonia.

What has the FDA decided about community-acquired pneumonia? Who knows as of this writing? They have issued draft (I emphasize draft) guidelines that, in my view, will make it extremely difficult if not impossible to carry out clinical trials in this disease. First, they require that no prior antibiotic be given. Scientifically, this is a sound decision since even a single dose of antibiotic can have a beneficial effect in pneumonia. In one recent trial, an antibiotic that was later found to be ineffective for pneumonia because it is actually inactivated in the lung looked successful among patients that had up to 24 h of effective prior antibiotic therapy but was clearly much less active among patients who had no prior therapy. Therefore, any experimental drug given after an effective antibiotic, even after only one or two doses, might look better than it really is. In fact, in recent trials, about 40% of patients had received at least one dose of another antibiotic before being enrolled in the trial. If those 40% had to be replaced with those who had no prior antibiotic, the trial would take much longer. For more serious cases of pneumonia, such as those now required by the FDA, it will be even harder to find patients with no prior antibiotic at all. Further complicating this requirement is a quality measure used for hospital accreditation for continued participation in Medicare and other reimbursement plans. This quality measure requires that the first dose of antibiotic be given for pneumonia within 6 h of the patient first being seen in the health care facility. Clearly, this will make it even harder to find untreated patients to enroll in clinical trials of antibiotics for pneumonia. The best solution to this problem is to allow only one or two doses of a prior antibiotic before entering patients into a trial for a new treatment. That would preserve most of the scientific integrity of the study and still allow a reasonable rate of enrollment. The analysis at the end of the study can then be stratified looking separately at those who had received prior effective therapy and those who had not. This approach would be a balance between perfect science and reality - a concept that seems to have escaped the FDA.

Second, the number of patients required has skyrocketed into the thousands further increasing the cost and the time it will take to run such a trial. The FDA has required that the new antibiotic demonstrate that it works only in those patients that have a documented (by culture) bacterial infection. Overall, in America, the number of cases of pneumonia that are documented by isolating the infecting organism is an astounding 7.5% (Medicare data). In recent clinical trials where we make heroic efforts to identify the bacterial pathogen, the diagnosis rate varies from 20 to 35% with an average of about 25%. Given these numbers and the FDA's statistical requirements, to gain approval of an oral drug for pneumonia would require studying over 5000 patients. My estimate is that the trials alone would take more than 5 years and that the data might be obsolete by the time the FDA actually approved the drug. The Infectious Diseases Society and the FDA recently held a workshop to discuss the use of modern diagnostics to boost the proportion of cases where the pathogen could be identified. It is clear that this is not an attractive market for diagnostics companies and that the pathway to approval for such a diagnostic test is not straightforward. One diagnostic company executive openly questioned whether "the juice is worth the squeeze." The only other way forward offered by the FDA that was at all practical was to propose the use of an investigational diagnostic method that would have to be considered on a case be case basis and where the implications for how the company would be able to promote the drug after using such a diagnostic test was unclear. The company might be stuck having to promote their antibiotic to be used only after a diagnosis had been established with an unapproved investiga-tional diagnostic test. The design proposed by the FDA is quite simply not feasible in today's world and no pharmaceutical company will undertake such a study.

Finally, the severity of illness to be treated has increased. There is some belief that patients with the mildest forms of pneumonia are more likely to get better without antibiotics, so the FDA would like to eliminate them as much as possible from clinical trials so that the antibiotic being investigated is appropriately challenged. The science behind this decision is, at best, controversial and this requirement will further slow trial enrollment rates and increase costs. Mild pneumonia tends to get worse without treatment.

Some of these FDA requirements may be scientifically justified, but they will help to assure that no or only very few new antibiotics will be developed for this important infection.

To make matters worse, Public Citizen has publicly called for a different endpoint altogether for studying community-acquired pneumonia - that of mortality. The proposal is scientifically based on the fact that the benefit of antibiotics in pneumonia was proven by looking at mortality rates in treated compared to untreated patients in the 1930s and 40s. This approach is completely irrelevant in the antibiotic age. The problem with this suggestion is that almost no one dies of pneumonia anymore because our therapy is so good - especially when considering the more common forms of pneumonia. Overall, for community-acquired pneumonia treated as an outpatient, the mortality ranges from 0.1 to 0.9%. For pneumonia that requires that the patient be hospitalized, it ranges from 0.9 to 26.7% - but those patients in the high mortality range are those admitted to the intensive care unit where antibiotics may not be much help anymore. These ICU patients usually have severe mechanical problems with their breathing from all the fluid in their lungs and other derangements. The overall mortality in trials of patients with community-acquired pneumonia is around 3%. So the proposal to use mortality as an endpoint for studying pneumonia would require enrolling from 7200 to over 100,000 patients in a trial. Again, this is a completely infeasible design.

PhRMA has an antimicrobial working group that has provided a response to the FDA's new proposed guidelines for clinical trial design in pneumonia. They have made suggestions that respond to the FDA's requirement for strong science and for microbiologically documented infection while providing for the feasibility of future trials. Because the industry is thought of as the devil incarnate in Washington and around the nation, politically, the FDA has no particular incentive to listen to them.

In fact, there was such a negative response to the FDA's draft guidelines for community-acquired pneumonia that they held yet another Anti-infectives Drug Advisory Committee (AIDAC) meeting in December of 2009. I was one of the presenters at the meeting. Prior to the meeting, I had submitted my presentation materials showing that the FDA had mandated clinical trial designs that were infea-sible. I pointed out that this was, in a way, irresponsible and misleading. They seem to have heard that message because in their summary, they recognized that the issuance of guidance requiring infeasible trials was not acceptable. The FDA also recognized that mortality was not the only acceptable endpoint for a clinical trial of pneumonia and they agreed with the world of physicians who said that one could tell whether a patient was responding to antibiotics for pneumonia by day 3 of therapy. These concessions could be a major turning point in our discussions with the FDA. I (and others, too) have communicated a trial design strategy that would allow for feasible trials and still achieve everything the agency would like in pneumonia. But I have been disappointed so often in the past that I won't break out the champagne until I see new guidance with feasible trial design requirements.

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