| Comment Record|
Dr. Frank Guerino ||
2002-05-06 11:48:23 |
Alpharma Inc |
| Comments for FDA General |
1. General Comments
To Docket: 02N-0027
Alpharma would like to thank the CVM for the opportunity to participate in and provide comments on the Swine Mycoplasma Pneumonia Workshop held on March 6 and 7, 2002. Listed below are some brief comments that we would like CVM to consider in developing requirements for evaluation of drug effectiveness against this important pathogen. We believe that these comments are consistent with those expressed by the independent experts present at the meeting.
Nature of the Claim:
We agree with the consensus at the Workshop that an appropriate therapeutic claim should be either for the reduction in the severity of pneumonia caused by Mycoplasma hyopneumoniae or for the control of pneumonia caused by Mycoplasma hyopneumoniae. Due to the chronic nature of the infection and the difficulty in completely eliminating the organism from the swine respiratory tract, we believe that the above wording would be an accurate reflection of the activity of presently available antibiotics.
Model Studies vs Field Studies:
Several of the scientists at the Workshop emphasized the fact that M. hyopneumoniae is an important pathogen in the porcine respiratory disease complex (PRDC) and that in the field, pneumonia associated with M. hyopneumoniae rarely if ever occurs in the absence of other pathogens. Furthermore, it is extremely difficult to reliably isolate M. hyopneumoniae for diagnostic purposes or to rely on pathological findings to differentiate lesions caused by the various bacterial or viral organisms that may be present in PRDC. These facts together with the various confounding factors that may be present in a field situation, make field studies an inappropriate design for evaluating drug effectiveness against this specific organism. We strongly believe that model studies are the only current method that can accurately evaluate effectiveness against M. hyopneumoniae in a controlled manner.
In model studies, pigs are typically inoculated with a pure culture of M. hyopneumoniae, thus allowing the researcher to make firm conclusions regarding the effectiveness of a drug against this specific organism. Unlike field studies, one can reliably use reduction in lung lesions as a valid clinical endpoint. This is not the case in field studies where multi-organism infections will be present. Field studies also suffer from a serious design flaw in that it will be extremely difficult to isolate the study animals from other animals.
An argument was made by some at the Workshop that performance data should be generated in field studies to demonstrate effectiveness against M. hyopneumoniae. We strongly disagree. This approach ignores the fact that many antibiotics are broad spectrum. In addition to having activity against other bacterial pathogens present in the lungs, they would also have growth promoting activity against organisms in the GI tract. Under these circumstances, performance benefits from reduction in M. hyopneumoniae infection would be confounded with the reduction of other pathogens and with growth promotion. Based on these and other uncontrollable factors, it is clear that field studies will result in many false positives as well as false negatives. Therefore, as provided for under ADAA, we strongly recommend that CVM limit in vivo effectiveness evaluations against M. hyopneumoniae to well-controlled model studies.
A significant portion of time at the Workshop was dedicated to discussion of the various diagnostic techniques that exist and are under development. Some, such as PCR, can definitively demonstrate the presence of M. hyopneumoniae. It was stated on numerous occasions by the various experts present that no reliable technique is currently available to determine a reduction in pneumonia caused by M. hyopneumoniae in a mixed bacterial and viral infection. This point again argues for the validity of model studies, where reduction in lung lesions is a valid clinical endpoint, over field studies. If demonstration of effectiveness in field studies were to become a requirement, then we are aware of no valid clinical endpoints nor do we recall that any were presented at the Workshop.
Based on the information presented at the Workshop and our knowledge of this disease, we suggest that model studies be used to demonstrate a reduction in the severity of pneumonia caused by a pure M. hyopneumoniae infection. The clinical endpoint for these studies should be reduction in lung lesions.