FINAL DECISION OF THE COMMISSIONER Docket No. 2000N-1571 WITHDRAWAL OF APPROVAL OF THE NEW ANIMAL DRUG APPLICATION FOR ENROFLOXACIN IN POULTRY

Enrofloxacin is an antimicrobial drug belonging to a class of drugs known as fluoroquinolones. On October 31, 2000 , the Center for Veterinary Medicine (CVM) of the U.S. Food and Drug Administration (FDA) published a Notice of Opportunity for Hearing (NOOH) proposing to withdraw the approval of the new animal drug application (NADA) 140.828 for the use of enrofloxacin in chickens and turkeys. Enrofloxacin for Poultry: Opportunity for Hearing (NOOH) , 65 Fed. Reg. 64,954 (2000).¹ On November 29, 2000, Bayer Corporation (Bayer), the sponsor of enrofloxacin (sold under the trade name Baytril® 3.23% Concentrate Antimicrobial Solution), requested a hearing on the proposed withdrawal. On February 20, 2002 , FDA's Acting Principal Deputy Commissioner published a Notice of Hearing (NOH) granting Bayer's request and identifying the factual issues that would be the subject of the evidentiary hearing. Enrofloxacin for Poultry: Notice of Hearing (NOH), 67 Fed. Reg. 7700 (2002). On March 21, 2002 , the Animal Health Institute (AHI) submitted a Notice of Participation pursuant to 21 CFR § 12.45, identifying itself in part as "the national trade association representing research based manufacturers of animal health products." AHI Notice of Participation (APE4) at 1.²

The participants filed joint stipulations on September 20, 2002 , and revised them in a submission on December 24, 2002 . CVM submitted documentary evidence and written direct testimony on December 9, 2002 , and Bayer and AHI submitted documentary evidence and written direct testimony on December 13, 2002 . On December 17, 2002 , the Administrative Law Judge (ALJ) granted the participants' motions to submit written direct testimony of witnesses and to move specific exhibits and documents into the evidentiary record of the hearing, subject to later motions to strike. (The ALJ handled subsequent requests concerning admission of evidence on a submission-by-submission basis.) Oral hearing for the purposes of cross-examination of witnesses was held at FDA from April 28 through May 7, 2003 . Following the hearing, the participants submitted post-hearing briefs, pursuant to 21 CFR § 12.96(a).

On March 16, 2004 , the ALJ issued an Initial Decision pursuant to 21 CFR § 12.120. The ALJ found, among other things, that more than a million people annually suffer from infections caused by Campylobacter, a genus of bacteria; that poultry is a source of Campylobacter infections; that the use of enrofloxacin in poultry results in the emergence and dissemination of fluoroquinolone-resistant Campylobacter; that fluoroquinolone-resistant Campylobacter in poultry can be transferred to humans and "can contribute to" fluoroquinolone-resistant Campylobacter infections in humans; and that fluoroquinolone-resistant Campylobacter infections in humans "have the potential to adversely affect human health." Initial Decision at 66-67. Based on these and other findings, the ALJ determined that "Bayer has not shown Baytril use in poultry to be safe[,]" id. at 66, as set out in § 512(e)(1)(B) of the Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. § 360b(e)(1)(B).

On May 17, 2004 , Bayer (jointly with AHI) and CVM each filed exceptions to the ALJ's Initial Decision, pursuant to 21 CFR § 12.125(a).³ Bayer's exceptions run to 234 pages and raise numerous legal and factual challenges to the ALJ's conclusions. CVM also filed exceptions, primarily challenging the ALJ's statements concerning evidentiary standards and burdens of proof and also seeking correction of some factual statements and findings by the ALJ. On July 16, 2004 , the participants filed responses to each other's exceptions. Large portions of Bayer's exceptions do not comply with 21 CFR § 12.125(b), which provides: "Exceptions must specifically identify alleged errors in the findings of fact or conclusions of law in the initial decision, and provide supporting citations to the record." Additionally, many of Bayer's exceptions are frivolous or trivial. Bayer's lengthy filing contains sentences, paragraphs, and even whole pages that completely lack any citation to the record.⁴

In its exceptions, Bayer requested oral argument before the Commissioner pursuant to 21 CFR § 12.125(b). Bayer Exceptions at 1. The request did not identify any specific issues to be addressed by oral argument. There is no right to oral argument under 21 CFR § 12.125(b) and (e). Because I do not find oral argument necessary, I am denying this request.

After reviewing the evidentiary record of the hearing, I find that the record supports the ALJ's determination under § 512(e)(1)(B) of the FDCA that enrofloxacin is not shown to be safe for use in poultry under the approved conditions of use. However, my reasoning varies in several regards from that of the ALJ. I therefore am withdrawing the approval of the NADA for use of enrofloxacin in poultry for the reasons set forth more fully in this Final Decision. This Decision supplants the Initial Decision except where it is specifically adopted.

As to exceptions filed by the participants, I am required by law and regulation to address only those exceptions by the participants raising "significant" issues. Nitrofurans; Withdrawal of Approval of New Animal Drug Applications (Nitrofurans), 56 Fed. Reg. 41,902, 41,903 (1991); Simpson v. Young, 854 F.2d 1429, 1434 (D.C. Cir. 1988); 21 CFR §§ 12.120(b) and 12.130(c). Exceptions by Bayer not specifically addressed in this Final Decision are overruled. I have addressed all legal and significant factual exceptions by CVM.

II. PRELIMINARY MATTERS

A. Statutory Standard

CVM proposed to withdraw approval of enrofloxacin pursuant to
§ 512(e)(1)(B) of the FDCA, which provides:

The Secretary shall, after due notice and opportunity for hearing to the applicant, issue an order withdrawing approval of an application filed pursuant to subsection (b) with respect to any new animal drug if the Secretary finds --

. . .

(B) that new evidence not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved ... .

21 U.S.C. § 360b(e)(1)(B).

I address exceptions regarding the ALJ's interpretation of this standard below.

B. Burden and Standard of Proof Issues

I agree with the Initial Decision's general description of the allocation of the burdens between CVM and Bayer. See Initial Decision at 5. CVM, as the proponent of withdrawal of approval of the use of enrofloxacin in poultry, has the burden of making the first showing; in other words, CVM has the initial burden of production. Hess & Clark, Inc. v. FDA, 495 F.2d 975, 992 (D.C. Cir. 1974); Diethylstilbestrol; Withdrawal of New Animal Drug Applications (DES), 44 Fed. Reg. 54,852, 54,861 (1979). Once this threshold burden has been satisfied, the burden passes to Bayer, as the sponsor of enrofloxacin, to demonstrate its safety. Rhone-Poulenc, Inc. v. FDA, 636 F.2d 750, 752 (D.C. Cir. 1980) (percuriam); Hess & Clark, 495 F.2d at 992; 21 CFR § 12.87(d).

I adopt the formulation of CVM's burden that FDA Commissioners have used in previous new animal drug withdrawal proceedings under § 512(e)(1)(B): "" ... [the Center] must provide a reasonable basis from which serious questions about the ultimate safety of [the drug] and the residues that may result from its use may be inferred.'" DES, 44 Fed. Reg. 54,852, 54,861 (quoting DES Initial Decision); Nitrofurans, 51 Fed. Reg. 41,902, 41,903, quotingDES; see alsoRhone-Poulenc, 636 F.2d at 572 ("We must therefore review the record in this case to determine whether the FDA has presented new evidence raising questions about the safety of DES that are sufficiently serious to require the manufacturers to demonstrate the drug is safe.")⁵ I note that this formulation does not, as Bayer occasionally states, require CVM to "demonstrate harm to human health." E.g., Bayer Exceptions at 80. That level of evidence is only required when CVM seeks to withdraw approval under § 512(e)(1)(A) of the FDCA because "experience or scientific data show that such drug is unsafe" under the approved conditions of use. 21 U.S.C. § 360b(e)(1)(A). DES, 44 Fed. Reg. 54,852, 54,861.

In its Exceptions, CVM challenged statements by the ALJ in the Initial Decision that the standard of proof that he was applying was preponderance of the evidence. CVM Exceptions at 1-3. CVM argues that the ALJ's findings must instead be based on "substantial evidence." Id. In responding, Bayer argues that CVM's burden is to show by a preponderance of the evidence that enrofloxacin is not shown to be safe; Bayer also argues that if the burden shifts, it then must show by a preponderance of evidence that enrofloxacin is safe. Bayer Reply to CVM Exceptions at 4.

I disagree with both CVM and Bayer. CVM's exceptions relate to the standard of proof (or quantum of evidence) that must support the ALJ's (and my) factual findings. Unless the substantive statute specifies otherwise, the standard of proof that the fact finder applies in administrative adjudications is the preponderance of the evidence standard. Steadman v. SEC, 450 U.S. 91, 96-102 (1980) (formal adjudication); Bender v. Clark, 744 F.2d 1424, 1429 (10th Cir. 1984) (informal adjudication). Here, I find that nothing in § 512(e)(1)(B) of the FDCA, which is the relevant substantive section, provides for a different result.⁶

Bayer's argument in its reply to CVM's exceptions deals, in part, with the burdens of production and persuasion. Bayer Reply to CVM's Exceptions at 4. CVM's initial burden of production in this withdrawal has already been well established by Final Decisions concerning prior new animal drug approval withdrawals. CVM's initial burden of production is to "provide a reasonable basis from which serious questions about the ultimate safety" of enrofloxacin can be inferred. DES, 44 Fed. Reg. 54,852, 54,861; Nitrofurans, 51 Fed. Reg. 41,902, 41,903, quotingDES; see alsoRhone-Poulenc, 636 F.2d at 572.

Moreover, it is not clear why Bayer describes a standard of proof as applying to the participants' respective burdens. By arguing that the standard of proof that applies to both participants' burdens is preponderance of the evidence, Bayer also seems to be implying that CVM has the burden of persuasion. Bayer Reply to CVM Exceptions at 4-5. If that is what Bayer means, I disagree. Bayer, as the sponsor of enrofloxacin, has the ultimate burden of persuasion regarding the safety of the drug. 21 CFR § 12.87(d); seealsoRhone-Poulenc, Inc., 636 F.2d at 752; Hess & Clark , 495 F.2d at 992. Bayer must satisfy the statutory standard of showing by "adequate tests by all methods reasonably applicable" that enrofloxacin is safe, 21 U.S.C. § 360b(b)(1)(A), (c)(1), & (d)(1)(A); in other words, Bayer must come forward with evidence that is sufficient to address CVM's safety questions.⁷

In sum, with respect the various issues raised by the participants on the burden of proof and standard of proof, I conclude that:

CVM bears an initial burden to produce evidence. CVM must show that there is a reasonable basis from which serious questions may be inferred about the ultimate safety of enrofloxacin use in poultry and any substance that may be formed in or on food as a result of such use.
If CVM carries its burden of production, Bayer, as the drug's sponsor, has the burden of persuasion on the ultimate question of whether enrofloxacin is shown to be safe. Bayer must do so, as set out in § 512(d)(1)(A) with "adequate tests by all methods reasonably applicable ... ." 21 U.S.C. § 360b(d)(1)(A).
As the fact finder, I must weigh the record evidence and make my factual findings based on the weight of the evidence. In other words, my findings must be supported by a preponderance of the evidence.

C. Scope of Commissioner's Review

21 CFR § 12.130(a) provides that "[o]n appeal from or review of the initial decision, the Commissioner has all the powers given to make the initial decision." 21 CFR § 12.130(b) provides that "[t]he scope of the issues on appeal is the same as the scope of the issues at the public hearing unless the Commissioner specifies otherwise." See also 5 U.S.C. § 557(b) ("[o]n appeal from or review of the initial decision, the agency has all the powers which it would have in making the initial decision except as it may limit the issues on notice or by rule").

In the NOH, the Acting Principal Deputy Commissioner, after reviewing Bayer's response to the NOOH, defined the factual issues that would be the subject of the hearing as follows:

Whether new evidence shows that enrofloxacin is not now shown to be safe for use under the conditions of use upon the basis of which the application was approved. This issue includes:

Whether there is a reasonable basis from which serious questions about the safety of enrofloxacin use in poultry may be inferred, such as:
1. Whether enrofloxacin use in poultry acts as a selection pressure, resulting in the emergence and dissemination of fluoroquinolone-resistant Campylobacter spp. [species] in poultry?
2. Whether fluoroquinolone-resistant Campylobacter spp. in poultry are transferred to humans and whether they contribute to fluoroquinolone-resistant Campylobacter infections in humans?
3. Whether fluoroquinolone-resistant Campylobacter infections in humans have the potential to adversely affect human health?
Whether the use of enrofloxacinunder the approved conditions of use in poultry has been shown to be safe?

67 Fed. Reg. 7700, 7701. This is an appropriate statement of the issues in this proceeding.⁸

D. Evidentiary Issues

Under 21 CFR § 12.94(c)(1)(i) and (d)(1)(i), the presiding officer may exclude written or oral evidence only if it "is irrelevant, immaterial, unreliable, or repetitive." See also 5 U.S.C. § 556(d) ( "the agency as a matter of policy shall provide for the exclusion of irrelevant, immaterial, or unduly repetitious evidence."). Under 21 CFR § 12.94(c)(3), written evidence excluded by the ALJ remains in the evidentiary record of the hearing.

1. Exclusion of evidence on relevance grounds

In an order dated March 3, 2003 , the ALJ, acting on motions to strike by the participants, struck in part or entirely several pieces of evidence. OR31 at 1. In this order, the ALJ held that "[r]isk/benefit evidence is relevant only to the extent it deals with human health effects, i.e.[,] whether the human health benefits of using the drug outweigh the human health risks from use of the drug," and stated categorically that "[e]conomic and environmental evidence is not relevant to the issues in this proceeding." Id . ; see also Initial Decision at 9. In light of this ruling, the ALJ struck on relevance grounds, among other testimony and exhibits, the written direct testimony of Mr. G. Thomas Martin, B-1907 (economic benefits), Mr. Steven Woodruff, B-1918 (environmental impact of withdrawal), and Dr. Robert Harris, B-1919 (indirect human health impact of environmental impact). Bayer challenges this ruling. Bayer Exceptions at 64-72.

For the reasons set out in section IV.B.2, I agree with the ALJ that evidence concerning economic benefits of enrofloxacin use, the environmental impact of withdrawal of approval, and the human health consequences of the environmental impact are irrelevant to withdrawal of approval of a new animal drug, but disagree with the ALJ to the extent the Order of March 3, 2003, or the Initial Decision allows for the consideration of alleged human health benefits of enrofloxacin.⁹ All evidence relating to any human health benefits of enrofloxacin also should have been stricken as irrelevant.¹⁰

I also agree with the ALJ that animal welfare is not relevant in assessing the safety of enrofloxacin. Initial Decision at 8-9 and 67 ("[i]n a NADA withdrawal proceeding, the effects of withdrawal on ... animal welfare are not relevant. ... Moreover, even if it were appropriate to consider enrofloxacin's withdrawal's effects on ... animal welfare, the evidence presented in this proceeding is insufficient to warrant such a finding."). No participant took exception to this finding. See Bayer Exceptions at 64 (challenging ruling with respect only to economic, environmental, and human health evidence).¹¹

2. Standards for reliability of evidence

Pursuant to 5 U.S.C. § 556(d), my findings must be "in accordance with the reliable, probative, and substantial evidence." Whether evidence meets this standard depends in part on the governing standard, which here is § 512(e)(1)(b). Here, as explained in section II.B, CVM's threshold burden under § 512(e)(1)(B) of the FDCA is to show that there are serious questions about the safety of enrofloxacin use in poultry. Contrary to Bayer's Exceptions, there is no checklist against which each individual study relied on by CVM must be evaluated to determine its reliability. See, e.g., Bayer Exceptions at 27-34. Rather, the evidence offered by CVM, taken as a whole, must be sufficiently reliable to satisfy CVM's limited statutory burden.

a. Applicability of Daubert v. Merrell Dow Pharmaceuticals, Inc.

As Bayer acknowledges, Bayer Exceptions at 28, the evidentiary standards set out in Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), and its progeny are not binding in administrative adjudications. SeePeabody Coal Co. v. McCandless, 255 F.3d 465, 469 (7th Cir. 2001); Sierra Club v. Marita, 46 F.3d 606, 621-22 (7th Cir. 1995); Stewart v. Potts, 996 F. Supp. 668, 678 n.8 (S. D. Tex. 1998). Daubert is not binding in this proceeding because the Federal Rules of Evidence, which it interprets, do not apply to administrative adjudications. E.g., Peabody Coal , 255 F.3d at 469.¹²

As will be clear in reviewing the discussion of the evidence below, however, the principles of Daubert are useful to this proceeding. Furthermore, I find that consideration of those principles leads me to conclude that the epidemiologic and other research CVM presented is reliable. These studies are helpful to me in understanding and deciding on facts in issue; the evidence is relevant; there is a general acceptance within the relevant scientific communities about the process and methodologies used in these studies; the data were generated apart from this administrative proceeding; the data were developed and presented in an open, transparent process; and most of the studies were either peer-reviewed and published or were subject to an equivalent public and expert review process. Cf. 509 U.S. at 591-595 (listing some of these factors as useful in determining reliability).

b. The Information Quality Act

Bayer also asserts that the FDA and Office of Management and Budget (OMB) guidelines issued pursuant to the Information Quality Act (IQA), Pub. L. No. 106-554, § 515 (2000), see 44 U.S.C. § 3516 note,¹³ provide "useful guideposts" for evaluating the testimony and evidence relied on by CVM. Bayer Exceptions at 31. Bayer further argues that a risk assessment relied on by CVM, described in more detail below, must satisfy FDA's guidelines to be considered reliable evidence in this proceeding. Id. at 32.

I disagree with both arguments. The stated intent of the IQA is to ensure and maximize the quality of data "disseminated" by Federal agencies and to allow "affected persons" to request correction of such information -- not to impose new evidentiary standards in administrative proceedings.¹⁴ Pub. L. No. 106-554, § 515. Indeed, OMB's guidelines specify that such requests for correction should serve to address the genuine and valid needs of outside parties without disrupting agency processes, 67 Fed. Reg. 8452, 8458, and information used in and findings made in adjudications are expressly exempted by the FDA Guidelines. See FDA Information Quality Guidelines, II.F. Furthermore, on its face, the FDA guidance makes clear that it, like all FDA guidance documents, does not "create or confer any rights for or on any person or bind FDA or the public." FDA Guidelines;¹⁵ see also 21 CFR § 10.115(d). Rather, the guidance "represents [FDA's] current thinking on this topic," and the document specifies that "[a]n alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations." FDA Guidelines.

The risk assessment, like all scientific evidence before me, will be evaluated to determine its strengths and weaknesses. I conclude, however, that the IQA Guidelines provide no independent set of mandatory standards by which the risk assessment, or any other evidence, must or even should be evaluated in this context.¹⁶ If I were to agree with Bayer's interpretation of the role of the FDA's IQA guidelines in this proceeding, I would in effect be ruling that in any formal administrative proceeding the IQA guidelines should replace longstanding and well-established statutory provisions and judicial doctrine about the admissibility and reliability of expert testimony and scientific evidence. Bayer's IQA argument would also require me to evaluate the evidence on which CVM relies differently from that on which Bayer relies. See Bayer Exceptions at 32 (" ... even if the FDA Guidelines are not strictly applicable to this proceeding, they do nevertheless inform the evaluation of the reliability of CVM's testimony and evidence in this proceeding." (emphasis added)). I do not believe that Congress would have chosen such an indirect means of changing the formal adjudication provisions of the APA and drug approval and withdrawal provisions of the FDCA. The factors I look to in evaluating the reliability of the scientific evidence do not change depending on which participant is relying on it.

c. Epidemiologic evidence

Finally, Bayer presents "several principles" that it claims epidemiologic studies "must satisfy" to be "reliable." See Bayer Exceptions at 28-31. These purported principles, which are largely unreferenced, confuse or misstate in several instances both applicable law and science, and I reject them without extended discussion.¹⁷ To the limited extent that Bayer provides legal references for its assertions, they consist of tort and product liability cases that do not involve the statutory standard at issue here. At best, the sweeping assertions that Bayer makes in reliance on these cases may reflect a court's position with respect to whether a particular piece of evidence might satisfy a party's burden in those actions .

That said, because much of the evidence at issue in this proceeding consists of epidemiologic data, I describe the nature of epidemiologic studies and identify some considerations helpful in evaluating the reliability of an individual study. Epidemiology is the study of "the incidence, distribution, and etiology of disease in human populations." Magistrini v. One Hour Martinizing Dry Cleaning, 180 F.Supp.2d 584, 590 (D.N.J. 2002) (quoting from Michael D. Green et al., Reference Guide on Epidemiology, in Federal Judicial Center, Reference Manual on Scientific Evidence at 335 (2d ed. 2000)); see also Feldman, B-1902 at 5 and 51 (Att. 1). Epidemiology is not focused on specific causation, in the sense of tracing an exposure to a particular individual's health outcome. 180 F.Supp. 2d at 590. Rather, its aim is to identify "agents that are associated with an increased risk of disease" or other outcome of interest. 180 F.Supp. 2d at 591.

Epidemiology encompasses a range of research methodologies, including both experimental and observational studies. In experimental studies, such as randomized controlled trials, subjects are randomly assigned by researchers in advance to treatments or exposures and compared with subjects who are assigned to a control or no exposure. Id . at 590. A clinical trial that evaluates the safety or efficacy of a therapeutic treatment is an example of an experimental study.

Observational studies are done to characterize the health and other outcomes of events or exposures without intervening to change the outcomes. In analytical studies, researchers evaluate the experience of a group exposed to an agent with respect to a particular health outcome (e.g., cancer), and compare it to the experience of a comparable group or groups of individuals that have not been exposed to the agent to identify and quantify associations, test hypotheses, and identify causes. This type of study often has a cohort study design, in that the experience of a cohort, or group, of exposed individuals is compared over time to the experience of a non-exposed group of individuals.

Another observational epidemiologic study design is the case-control study, in which individuals who are classified as "cases" having the disease or outcome of interest are compared with "controls" that do not have the disease or outcome of interest. Cases and controls are typically matched for similarity by age, sex, or other factors. The purpose of case-control studies is to investigate what differentiates the cases from the controls. For example, an outbreak of food poisoning linked to an event like a luncheon served at a conference can be investigated by comparing the foods the people who got sick ate with the foods the people who did not get sick ate. In this way, exposures that may differentiate the risk associated with being a case are identified.

In case-control studies involving sources of suspected foodborne illness, scientists often question cases and controls about their food intake and other exposures in the time period shortly before occurrence of symptoms in the cases. Wegener, G-1483 at 12. Limitations of this study design include the fact that no information is available beyond what was asked of the study participants and what is within their knowledge (for example, they would not know what the food handling practices were in the kitchens of restaurants in which they ate). There is also a possible difference in how well or how accurately cases and controls remember foods they ate in a particular period of time. There may be differences in the timing of questioning of cases and controls that can affect the quality of their recall. Differences in accuracy or completeness of recall between cases and controls may introduce a systematic error into the results. Feldman, B-1902 at 27; see, e.g., Angulo, G-1452 at 93 (Att. 3) (discussing possible sources of bias in a case-control study of foodborne illness). Another issue with observational case-control studies is that it can be difficult to discern differences in risk when an exposure is common among both cases and controls; for example, asking subjects whether they ate chicken in a particular time period. See Wegener, G-1483 at 12. Measures to reduce the risk of not finding a difference in exposure between cases and controls when such a difference actually exists include increasing the size of the study, since with a very large number of cases and controls small differences between the two groups can be detected. Id . at 13.

In general, the design, conduct, statistical methods, and data analysis of an individual epidemiologic study should be evaluated to determine the reliability of the study's conclusions. In addition, a number of criteria may be relevant in evaluating whether an individual study or group of studies establishes an association between an exposure and an outcome. These criteria include temporal relationship; strength of the association; the existence of a dose-response relationship; whether the relationship is consistent across different studies and in different populations; whether the association is biologically plausible; whether alternative explanations have been taken into account and eliminated or controlled for; whether the outcome changes when exposure changes; the specificity of the association; and whether the findings of the relationship are consistent with other data. Magistrini, 180 F.Supp. 2d at 592-593. One or more of these factors may be absent even where a causal relationship exists, and no one factor is necessary to establish an association between an exposure and an outcome. Id . at 592 n. 9.

Epidemiologic studies often are designed to evaluate a pre-defined hypothesis; for example, researchers may hypothesize that there is a real difference in exposure to a risk factor between cases and controls, or a real difference in the observed incidence of an event among the exposed compared with the non-exposed. An example of such a hypothesis might be that consumption of drinking water from a certain municipal well is associated with an elevated risk of cancer. Researchers use a statistical concept called "statistical significance" to quantify the likelihood that the observed differences between cases and controls could have been due to chance, rather than to a true association between exposure and health outcome. Researchers often judge the statistical significance of a study result in terms of the magnitude of the "p-value," which is derived from statistical analysis or statistical testing of the researchers' hypothesis on the data observed. Traditionally, a p-value of 0.05 or less indicates that the observed results are not likely due to chance. In general, the smaller the p-value, the more "significant" a result is, in the sense that the possibility that the association (outcome) is due to chance is lowered (because, when the p-value is 0.05, there is still a 5%, or 1 in 20, chance that the result is a false positive and does not actually reflect a difference between cases and controls). Tr. at 60.

Statistical uncertainty is also sometimes reported by researchers by a "confidence interval" or "CI," which reflects the upper and lower limits of an interval, calculated from the observed data, which is likely 95% of the time to contain or cover the true value of the mean, proportion, or rate of interest. See Last JM, (ed.), A Dictionary of Epidemiology (Third Edition), New York , Oxford University Press, 1995 at 35.¹⁸ So, for example, when CVM witness Dr. Frederick Angulo testified that " [i]n the multivariate logistic regression model, the proportion of Campylobacter isolates¹⁹ resistant to [fluoroquinolones] in 2001 ... was 2.5 times higher (95% confidence interval, 1.4 to 4.4 times higher) than the proportion of Campylobacter isolates resistant to [fluoroquinolones] in 1997," Angulo, G-1452 at 8, he communicated that the true value of the proportion of resistant isolates in 2001 compared with 1997, estimated to be 2.5 times higher (i.e., 150% higher), had a 95% likelihood of being within the interval that was at least 1.4 times higher (40% higher) and not more than 4.4 times higher (340% higher).

Of equal importance in the evaluation of epidemiologic studies is the impact of bias on the measures of association or risk. Such bias can derive from defects or limitations in the study design, the study's conduct, data analysis, matching strategies, or interpretation of the results. These factors might impact the existence, direction (i.e., positive or negative), statistical significance, or size of an association (i.e., the magnitude of the association between an exposure and the health outcome). Statistical significance alone cannot be relied upon to exclude bias as a plausible explanation for a study finding. Instead, in-depth analysis and evaluation of epidemiologic studies is always necessary to support the strength of the conclusions and to understand and explain the underlying limitations.

The participants stipulated that FDA is committed to following "well recognized principles of epidemiology." Revised Joint Stipulations 28 (CR2). While the participants did not specify to what precise principles they were referring, the principles for evaluating the strength of a particular epidemiologic study described in the preceding paragraphs are well-recognized in the field of epidemiology. See, e.g., Last at 77 (describing "Hill's criteria of causation").

As noted above, under § 512(e)(1) of the FDCA, I must withdraw approval if I determine that new evidence, "evaluated together with the evidence available ... when the [drug] was approved, shows that such drug is not shown to be safe ... ." 21 U.S.C. § 360b(e)(1)(B). In the proceeding before me, each piece of scientific evidence will have its own strengths and limitations. As a matter both of science and of law, the issue is whether a preponderance, or the weight of, the record evidence, taken as a whole, supports my decision. Cf. Public Citizen Health Research Group v. Tyson, 796 F.2d 1479, 1489, 1490 (D.C. Cir. 1986) (despite some limitations to each epidemiologic or animal study relied on in OSHA proceeding, cumulatively they provided "compelling" evidence of carcinogenicity).

3. Exclusion of the testimony of Dr. Louis Anthony Cox, Jr.

In the Initial Decision, the ALJ excluded the testimony of Bayer witness Dr. Louis Anthony Cox, Jr., an expert in risk analysis. Dr. Cox was one of eight witnesses cross-examined during a hearing held from April 28, 2003 , through May 7, 2003 . See Tr. at 843-1120; Cox, B-1901. The ALJ held that Dr. Cox's testimony lacked credibility and was unreliable. Initial Decision at 15.

I agree with the ALJ's determination that Dr. Cox's credibility was such that his testimony was so unreliable that it was inadmissible. The ALJ found that Dr. Cox's credibility was "severely compromised" because he intentionally misquoted published articles. Initial Decision at 15; see Tr. at 947-980. The ALJ found that some of Dr. Cox's quotes contained edits that went well beyond punctuation. Id. ("It seems that Dr. Cox edits referenced materials, prefers his versions to the originals, and quotes the edited version in his testimony.") On cross-examination, Dr. Cox acknowledged that his method of quoting from a particular research article in his written direct testimony did not comport to the standards he would have used for citing the paper in a journal article. Tr. at 967. Rather, he testified that in quoting from the article for his written direct testimony his "emphasis was on finding the supporting quote and giving it in enough detail and adequate citation so that everyone could see what I was talking about. And so that's a somewhat different context from a journal article, for example." Tr. at 967-968. Equally disturbing, Dr. Cox similarly stated that the quotation marks in a description he wrote of CVM's risk assessment as being based on ""average exposure for an average individual,'" see Cox, B-1901 at 25 (Att. 1), did not necessarily reflect a quotation attributable to CVM, but rather were included because he was "pretty sure that I was using their phrase," Tr. at 1002, and that he had "stuck that in quotes in my testimony because it seemed to be an important concept." Tr. at 1003. The ALJ determined, Initial Decision at 15, and I agree, that it should not be incumbent on a fact-finder to have to compare a witness's quotes from a published research article or other source against the original to determine if it appropriately characterizes or quotes from the original.

Bayer argues that the exclusion of Dr. Cox's testimony "favors form over scientific substance." Bayer Exceptions at 44. I am disturbed by this argument, and by Dr. Cox's own explanation of his actions. FDA expects witnesses in adjudications (formal or informal) to follow basic, accepted rules of attribution (e.g., when using quotation marks, the material should, in fact, be an accurate quote).

To ensure a complete record in the event of judicial review, I have nonetheless reviewed Dr. Cox's testimony, and it is discussed more fully below.

III. DISCUSSION

In this section I first describe the illness caused by Campylobacter infections in the United States , including how common such infections are, what the symptoms and complications are, and how they are treated. I then discuss the link between the use of enrofloxacin in poultry and human infection with Campylobacter, including infections that are resistant to fluoroquinolones. Finally, I discuss the impact on humans of infection with Campylobacter that are resistant to fluoroquinolones.

A. Human Campylobacter infections in the United States

1. Nature and public health impact of Campylobacter infections

The U.S. Centers for Disease Control and Prevention (CDC) estimated in 1999 that foodborne infections cause 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths each year. G-410 at 1; Tollefson, G-1478 at 3; Tauxe, G-1475 at 2. Foodborne illnesses may be caused by viruses, bacteria, parasites, toxins, metals, and prions. G-410 at 1; Tauxe, G-1475 at 2. CDC estimated that bacterial agents are associated with approximately 30.2% of foodborne illnesses and a majority of resulting hospitalizations (59.9%) and deaths (71.7%). G-410 at 5 (Table 3).²⁰

Campylobacter is a genus of bacteria with many different species, a number of which are known to cause illness in humans, although two, Campylobacter jejuni (abbreviated as C. jejuni) and Campylobacter coli (C. coli), are identified as the cause of almost all cultured human infections. Tauxe, G-1475 at 2; Nachamkin, G-1470 at 3; G-444 at 20-43, 85-104, and 105-136. Campylobacter is recognized as a leading cause of gastroenteritis²¹ in many developed and developing countries. Endtz, G-1457 at 2; G-1743 at 42. In the United States, the most important, in terms of human infection, is C. jejuni. Tauxe, G-1475 at 2; Jacobs-Reitsma, G-1459 at 2; Nachamkin, G-1470 at 3. C. jejuni and C. coli are difficult to differentiate in laboratory analysis, Nachamkin, G-1470 at 3 (5-10% of Campylobacter infections reported as C. jejuni are actually caused by C. coli), and the exact species of Campylobacter may not be identified in clinical laboratory settings. Tr. at 346.

Quantifying the burden of Campylobacter infections in the United States population is difficult because many people who become ill with gastroenteritis do not seek medical care. Revised Joint Stipulation 20; Tauxe, G-1475 at 2; Angulo, G-1452 at 6-7. Furthermore, even if a health care provider is consulted, many patients are not asked to provide a stool sample for culture to identify the presence of disease-causing bacterial pathogens. Tauxe, G-1475 at 2; G-1790 at 7. Finally, even where a specimen is obtained and cultured, positive cultures may not be reported to public health authorities, Tauxe, G-1475 at 2; Angulo, G-1452 at 6, and, as a result, are not tracked.

Based on data from 1996-1997 (adjusted for underreporting), in 1999 CDC estimated that 2.4 million illnesses in the United States each year are caused by Campylobacter, of which approximately 80% were foodborne infections. G-410 at 4-5; Angulo, G-1452 at 7; Tauxe, G-1475 at 2. In that analysis, CDC estimated that about 14.2% of foodborne illness in the United States annually is caused by Campylobacter infection, making it the leading bacterial source of foodborne illness in this country. G-410 at 5.

Almost all cases of campylobacteriosis in the United States are sporadic, i.e., they are unrelated to each other by a shared source of infection.²² Angulo, G-1452 at 9; Wegener, G-1483 at 12; Endtz, G-1457 at 3; Tauxe, G-1475 at 6. According to CVM witness Dr. Herbert Endtz , "Campylobacter leading to sporadic infections can be transmitted by several different routes, the relative importance of which varies with time and location ... . In developed countries poultry is often considered to be the most important reservoir of C. jejuni." Id . at 4; see also Wegener, G-1483 at 12-15. The role of poultry as a risk factor for human campylobacteriosis is discussed more fully below.

Annual incidence²³ of Campylobacter infections has declined since 1996-1997, when the data analyzed in the 1999 CDC report were collected. In a 2000 publication, Tauxe reported a decline in incidence of reported, laboratory-confirmed Campylobacter infections from 25.2 per 100,000 people in 1997 to 17.3 per 100,000 in 1999. Endtz, G-1457 at 2, citing G-1743 at 42. In April 2002, CDC reported that the bacterial pathogens with the highest relative incidence during 1996 to 2001 were Salmonella, Campylobacter, and Shigella. G-1791 at 2.²⁴ Over that time period, Campylobacter infections decreased 27% (95% CI 19-35%),²⁵ as did infections caused by other foodborne bacterial pathogens. Id. at 2-3. CDC noted that "the declines in the incidence of these foodborne infections occurred in the context of several control measures, including the implementation of the U. S. Department of Agriculture's (USDA) Food Safety Inspection Service (FSIS) of the Pathogen Reduction/Hazard Analysis Critical Control Point (HACCP) systems regulations in meat and poultry slaughter and processing plants." Id. at 3; see also G-1743 at 42. Bayer concurs that these and other food safety efforts, including "poultry safety labeling, FDA approval of poultry irradiation, improved consumer preparation and handling practices, and changes in poultry marketing and distribution" have reduced the risk of foodborne Campylobacter infections. Bayer Exceptions at 167-168; see also Minnich, G-1467 at 10-11. Using 1999 data and a simulation procedure, in the 2000 publication CDC estimated that the annual burden of foodborne Campylobacter infections is about 1.4 million. Angulo, G-1452 at 7 (citing an in-press publication).

Thus, although the incidence of these infections has declined in recent years, I find that the record demonstrates that Campylobacter infections remain a major cause of foodborne illness in the United States.

2. Symptoms and complications of Campylobacter infections

Campylobacter infections in humans are characterized by fever, headache, abdominal pain, and diarrhea (bloody or watery), usually 24-72 hours after ingestion of the contaminated food. Nachamkin, G-1470 at 2, Thielman, G-1477 at 2. Less frequently, patients may suffer from muscle aches and vomiting. Thielman, G-1477 at 2.

Campylobacter infection in humans can be self-limiting, i.e., it may resolve without antibiotics or other pharmaceutical treatment. Revised Joint Stipulation 19; Nachamkin, G-1470 at 2; Endtz, G-1457 at 2, 6. However, in some patients the illness may be prolonged or more severe. Nachamkin, G-1470 at 2; Endtz, G-1457 at 2, 6. In addition, Campylobacter infections can occasionally result in significant and sometimes long term adverse health outcomes. First, extraintestinal infections, such as meningitis, peritonitis, and bloodstream infection, are possible, although rare. Nachamkin, G-1470 at 3; Thielman, G-1477 at 2; Endtz, G-1457 at 2-3; Tr. at 289-290.

More commonly, Campylobacter infection can cause reactive arthritis and Guillain-Barré syndrome (GBS). Thielman, G-1477 at 2; Endtz, G-1457 at 3. Reactive arthritis, with pain and joint swelling, occurs within 2 weeks of infection. Nachamkin, G-1470 at 3. Incidence of reactive arthritis is uncertain, but has been estimated to range from 10-30 per 1,000 Campylobacter infections. Endtz, G-1457 at 3. GBS is characterized by a sudden onset of paralysis that in 20-35% of cases leaves patients unable to breathe without a respirator. Endtz, G-1457 at 3, 5-6. Most patients with GBS slowly recover within a year of onset, Endtz, G-1457 at 3; Nachamkin, G-1470 at 3, although about 20% have residual health problems and about 3-8% die from the illness. Endtz, G-1457 at 3. GBS is estimated to annually affect about 1-3 persons per 100,000 people. Endtz, G-1457 at 3; G-444 at 171. GBS is triggered by C. jejuni infections in 25-30% of cases in Europe and the United States, and up to 75% of cases in China and the Caribbean. Endtz, G-1457 at 3. Among people with Campylobacter infections, an estimated one in a thousand develops GBS. Tauxe, G-1475 at 3; Endtz, G-1457 at 3; G-444 at 174.

Finally, there is a very low possibility of death associated with Campylobacter infections. Mortality in the United States associated with Campylobacter is low, with estimates ranging from 8 per 10,000 to 24 per 10,000. Endtz, G-1457 at 2; see also B-205 at 7; Nachamkin, G-1470 at 3.

Campylobacteriosis cannot be distinguished clinically from illness caused by Salmonella, Shigella, and some E. coli bacteria; in other words, the symptoms are very similar and the causal agent cannot be ascertained without laboratory stool analysis. Thielman, G-1477 at 2. The similarity among these infections complicates diagnosis and treatment, as discussed more fully below.

I find that campylobacteriosis is a gastrointestinal illness characterized by fever, headache, abdominal pain, and diarrhea (bloody or watery). Although it usually resolves without treatment, complications occur, including secondary infections, reactive arthritis, and GBS.

3. Treatment of Campylobacter infections

For patients with a normal immune system who are not at the extremes of age or have other chronic diseases, antibiotic therapy is not generally indicated for treatment of mild Campylobacter infection. Ohl, G-1485 at 9-10. However, I find that the record demonstrates that certain groups of patients, including the very young, the elderly, the immunocompromised, and people with certain chronic diseases, should be treated, as should people with severe illness. Ohl, G-1485 at 7, 9-11; Revised Joint Stipulation 42; Endtz, G-1457 at 6; Nachamkin, G-1470 at 2; G-172 at 7.²⁶

When treatment is indicated, most practicing physicians will begin empirical antibiotics without waiting for stool culture results, in order to mitigate symptoms promptly, reduce the rate of recurrence, and decrease the risk of associated complications.²⁷ Thielman, G-1477 at 2-3; Endtz, G-1457 at 6; Ohl, G-1485 at 7-8, 10-11. There are "many obstacles to the identification of a bacterium that might be causing a diarrheal illness," Ohl, G-1485 at 8, including the inconvenience of obtaining a sample during an emergency room or physician visit, delays in culturing of the specimen in the laboratory, and the low diagnostic yield of stool cultures, id. As a result, many physicians do not order a stool culture at all, even for patients who present with diarrhea. Ohl, G-1485 at 8; Morris, G-1469 at 5.

Antibiotic therapy shortens the duration of illness or bacterial shedding, reduces the intensity of symptoms, and prevents complications. Ohl, G-1485 at 10-13; Thielman, G-1477 at 2-3. Treatment of gastroenteritis is more effective if begun early in the course of disease. Morris, G-1469 at 4-5; Thielman, G-1477 at 2-3; Endtz, G-1457 at 6. Early treatment may have a greater impact on resolution of symptoms than delayed treatment. Thielman, G-1477 at 2-3. In addition, if illness is prolonged, patients may be prone to further complications, including death. Thielman, G-1477 at 4-5.

I find that the record demonstrates that fluoroquinolones, such as ciprofloxacin,²⁸ are widely used to treat gastroenteritis, because they are generally well-tolerated, can be prescribed on an outpatient basis, and are effective against a broad range of bacteria. Nachamkin, G-1470 at 6; Thielman, G-1477 at 4.²⁹ Because treatment of gastroenteritis with antimicrobials begins before the results of fecal culture become available (or in the absence of a fecal culture), fluoroquinolones are the preferred antibiotics used to treat serious infections and as an empiric therapy for travelers' diarrhea and diarrhea of unknown cause. Endtz, G-1457 at 6-7; Nachamkin, G-1470 at 6; Ohl, G-1485 at 11-13; Thielman, G-1477 at 3; Morris, G-1469 at 5-6. Practice guidelines for clinicians, including the Infectious Diseases Society of America's "Practice Guidelines for the Management of Infectious Diarrhea," specifically recommend consideration of a fluoroquinolone for adults. Thielman, G-1477 at 3; see G-261 (IDSA guidelines) at 11-13; see also G-244 at 2.

4. Public health surveillance for Campylobacter

An important source of data on Campylobacter in the United States is the Foodborne Diseases Active Surveillance Network (FoodNet), which is a collaborative project among CDC, FDA, FSIS, and state health departments. Angulo, G-1452 at 2. FoodNet was set up "to determine the frequency and severity of foodborne diseases; determine the association of common foodborne diseases with eating specific foods; and describe the epidemiology of new and emerging bacterial, parasitic, and viral foodborne pathogens." Id. FoodNet uses population-based active surveillance for clinical laboratory isolations of a number of bacterial pathogens in a growing number of states and selected counties. Id. In 2001, the total population in the area under surveillance was more than 37 million people, or more than 13% of the United States population. Id.; G-1791 at 1.

The National Antimicrobial Resistance Monitoring System, or NARMS, monitors antimicrobial resistance trends in human, animal, and retail meat isolates.³⁰ Tollefson, G-1478 at 4-5, 14. NARMS was formed in January 1996 and also is a collaborative effort of the federal and state entities involved with FoodNet. Id. at 14; Angulo, G-1452 at 2-3. In part, NARMS was developed to evaluate the consequences of the approval of fluoroquinolone use in poultry. Tollefson, G-1478 at 14. Although NARMS surveillance is generally somewhat broader than the FoodNet surveillance framework, the NARMS surveillance specifically for Campylobacter is done within the context of FoodNet. Tr. at 296. Details about data generated through FoodNet and NARMS are discussed in the text.

B. Enrofloxacin use and Campylobacter in poultry

1. Approval and use of enrofloxacin in poultry

On October 4, 1996, FDA approved NADA 140-828 under § 512 of the FDCA, authorizing the use of enrofloxacin (Baytril® 3.23% Concentrate Antimicrobial Solution) to control mortality in chickens associated with Escherichia coli (E. coli) and mortality in turkeys associated with E. coli and Pasteurella multocida (fowl cholera). Revised Joint Stipulation 39.³¹ FDA approved the use of enrofloxacin only by prescription and under veterinary supervision, and only for therapeutic treatment (i.e., not for growth promotion). Revised Joint Stipulations 15-16. FDA prohibited the extra-label³² use of enrofloxacin for all food-producing animals, including poultry. Revised Joint Stipulations 17, 46.

The antibiotic is administered in the drinking water provided to an entire house of broiler chickens or turkeys if there is evidence that the disease is present. McDermott, G-1465 at 6-7; A-54. The participants stipulated that "FDA has long accepted drinking water delivery as a safe and effective means to administer therapeutic animal drugs, including antibiotics, to commercially grown broiler chickens and turkeys," Revised Joint Stipulation at 18, and that for commercially grown broiler chickens and turkeys in the United States, it is not feasible or practical to administer enrofloxacin to individual birds. Revised Joint Stipulation at 36. However, this method results in the treatment of birds that are not infected, and can also lead to underdosing of infected birds. Tr. at 29; McDermott, G-1465 at 6-7; G-52 at 28-29 (Baytril product information noting risk of underdosing). Such underdosing increases the probability of selecting for fluoroquinolone-resistant Campylobacter in both healthy and diseased birds. McDermott, G-1465 at 7; B-868 at 3.

FDA's approval does not limit either the proportion of annual poultry production or the number of birds that may be treated with enrofloxacin. A-54. Use varies both geographically (i.e., some regions may use more enrofloxacin than others) and over time, depending on the prevalence of disease in the poultry. See Hofacre, A-202 at 10-11 (describing regionality/seasonality of E. coli infections); Wages, B-1917 at 10 (in turkeys, "[o]utbreaks of E. coli and Pasteurella multocida infections tend to be regional and can be cyclical.") Bayer estimated that, of the poultry flocks that produce the 8.5-8.6 billion broilers and 270-272 million turkeys slaughtered each year, Hofacre, A-202 at 3; Revised Joint Stipulations 43, 44, 1- 2% of broiler flocks and about 4% of turkey flocks are treated with enrofloxacin annually, Bayer Exceptions at 3, 72; see A-192 at 3.³³ Therefore, the relatively small proportion of treated flocks translates to consumption of a relatively large amount of poultry meat from broilers and turkeys exposed to enrofloxacin.

2. Campylobacter colonization of poultry

Campylobacter , in particular C. jejuni and C. coli, are commonly found in the intestinal tracts of poultry, as well as cattle, swine, and other warm-blooded animals. Wegener, G-1483 at 2; White, G-1484 at 2; Jacobs-Reitsma, G-1459 at 2. In poultry, Campylobacter are commensal, i.e., they do not generally cause illness in the birds. Jacobs-Reitsma, G-1459 at 2; White, G-1484 at 2. Broilers usually become colonized at about two weeks of age or later.³⁴ Jacobs-Reitsma, G-1459 at 3-5; Newell, B-1908 at 5. Turkeys are colonized at between seven and fifteen days of age. Jacobs-Reitsma, G-1459 at 4; G-686 at 2. The source of the initial colonization is unclear, but is likely to be exposure to other animals on the farm (including poultry), wild birds, rodents, insects, or contaminated drinking water. Jacobs-Reitsma, G-1459 at 3; Newell, B-1908 at 6-10. After the initial infection, colonization of the entire poultry house occurs quickly; Campylobacter is generally isolated from close to 100% of the birds in flocks that test positive. Jacobs-Reitsma, G-1459 at 4; G-686 at 2. Although not all flocks are colonized by Campylobacter, the record shows that in the United States and elsewhere such colonization is very common. Jacobs-Reitsma, G-1459 at 3-5; Newell, B-1908 at 3; G-1724 at 3; G-385 at 1.

Once chickens and turkeys are colonized by Campylobacter, they excrete large numbers of Campylobacter in their feces until slaughter. Jacobs-Reitsma, G-1459 at 2-4, 7; Newell, B-1908 at 5.³⁵ Birds in poultry houses are exposed to the feces of other birds through direct consumption, contaminated water, and feed in open systems. Jacobs-Reitsma, G-1459 at 4. Because poultry houses in the United States are not cleaned to the floor between flocks, Carey, G-1456 at 3, birds may be exposed to contaminated litter and manure remaining in a poultry house from previous flocks, Jacobs-Reitsma, G-1459 at 3. The concentration of Campylobacter on the feathers and skin of poultry and the proportion of birds contaminated may increase substantially during transportation as a result of fecal shedding and reuse of inadequately cleaned transportation crates. Jacobs-Reitsma, G-1459 at 5. Campylobacter from colonized birds can also cross-contaminate birds originally free of Campylobacter at many points during the slaughter process. Minnich, G-1467 at 7-9; Logue, G-1464 at 2.

The record demonstrates that Campylobacter contamination remains on poultry after slaughter. For example, FSIS periodically conducts microbiological surveys of poultry carcasses. FSIS data indicate that C. jejuni/ C. coli was recovered from 90% of analyzed samples taken from 1,221 young turkey carcasses collected in 1996-1997 and C. jejuni/ C. coli was recovered from 88% of 1,297 chicken broiler carcasses collected in 1994-1995, G-651 at 6, 15; G-652 at 6, 15; White, G-1484 at 5. FSIS estimated in 1996 that the national prevalence of C. jejuni/ C. coli on raw ground chicken and raw ground turkey would be 60% and 25% positive, respectively, if the total volume of all federally inspected poultry meat were analyzed. White, G-1484 at 5; G-653 at 2, 8; G-654 at 2, 8. Other data on contamination of retail poultry meat products are discussed below.

Furthermore, in the same manner in which Campylobacter spreads among birds and flocks, flocks in which selection for fluoroquinolone-resistant Campylobacter has occurred may pass along resistant bacteria to other birds exposed to contaminated litter and manure and to chickens and turkeys during transport and slaughter. Minnich, G-1467 at 7-9, 11; Jacobs-Reitsma, G-1459 at 6. Once birds are colonized with fluoroquinolone-resistant Campylobacter, they remain colonized until slaughter. B-868 at 3-4; Jacobs-Reitsma, G-1459 at 6; McDermott, G-1465 at 3. Thus, I find that the evidence about colonization of turkey and chicken with Campylobacter is relevant to the issue of fluoroquinolone-resistant Campylobacter as well. More specific evidence that broilers and turkeys are contaminated with fluoroquinolone-resistant Campylobacter is discussed more fully below.

In sum, this evidence demonstrates, with respect to both fluoroquinolone-susceptible and -resistant Campylobacter, that Campylobacter colonization of poultry is widespread, that Campylobacter concentrations on live poultry and carcasses may increase as a result of current transportation and slaughtering practices, and that through these practices Campylobacter spread to birds that were previously free of Campylobacter. While the presence of high levels of these bacteria in live poultry and poultry carcasses is not proof in and of itself that Campylobacter infections in humans are associated with Campylobacter in poultry, it is a part of the chain of evidence leading to that conclusion.

3. Mechanism of fluoroquinolone resistance in Campylobacter and selection of resistant bacteria in poultry

Development of antimicrobial resistant bacteria is a hazard associated with antimicrobial drug use in both human and veterinary medicine. Tollefson, G-1478 at 2. With respect to Campylobacter, resistance to fluoroquinolones develops as a spontaneous genetic mutation.³⁶ Revised Joint Stipulation 1. In Campylobacter, a single point mutation in the gyrase gene (gyrA) occurs naturally in approximately 1 to 5 in 100 million bacterial cells. McDermott, G-1465 at 4-5; Newell, B-1908 at 12-13 (natural or spontaneous mutation). Thus, given the large numbers of Campylobacter present in colonized broilers and turkeys, Jacobs-Reitsma, G-1459 at 2; McDermott, G-1465 at 5, it is likely that this relatively rare spontaneous mutation will result in small numbers of resistant Campylobacter in the gut flora of nearly all Campylobacter-colonized chickens and turkeys. McDermott, G-1465 at 5. Therefore, when a Campylobacter-colonized chicken or turkey is treated with enrofloxacin, the antibiotic will kill susceptible target and non-target bacteria (including susceptible Campylobacter) in the gut flora of the treated birds, Levy, G-1463 at 7, but the few Campylobacter that are present that are not susceptible to fluoroquinolones (i.e., that are resistant to fluoroquinolones due to the spontaneous mutation) are not killed, and instead find themselves in an environment devoid of competing bacteria that they can and do quickly take over, re-colonizing the intestinal tract of the treated birds with resistant Campylobacter, Levy, G-1463 at 7; McDermott, G-1465 at 5; Barrett, G-1453 at 2; G-315; B-868; G-1800. This is referred to as "selection pressure." I find the record establishes that fluoroquinolone use in chickens and turkeys acts as a selection pressure for fluoroquinolone-resistant bacteria in the chicken and turkey digestive tract. McDermott, G-1465 at 2-4; Newell, B-1908 at 12; Revised Joint Stipulations 1, 7, 45 (stipulating that fluoroquinolone use can act as a selection pressure); see also Bayer Exceptions at 211.

Laboratory research conducted after fluoroquinolone use in poultry was approved show that fluoroquinolone treatment at therapeutic levels quickly selects for fluoroquinolone-resistant Campylobacter. When this selection occurs in a live bird, the fluoroquinolone-resistant bacteria quickly come to dominate. In one study, McDermott and colleagues investigated the impact of enrofloxacin (used according to label directions) on the development of fluoroquinolone resistance in the gut of broiler chickens. McDermott, G-1465 at 2-3; B-868. They found that within 24 hours of treatment with enrofloxacin, C. jejuni in the chickens became seven times more resistant to ciprofloxacin and enrofloxacin than they were before treatment.³⁷ Id . Furthermore, the researchers found that resistance persisted through the life span of the flock. McDermott, G-1465 at 3; B-868 at 3-4. In a control group of chickens also inoculated with C. jejuni but not treated with enrofloxacin, no fluoroquinolone-resistant Campylobacter were detected (that is, the resistant Campylobacter resulting from spontaneous mutation were below the level of detection), McDermott, G-1465 at 3; B-868 at 2-3, indicating that the dominance of resistant microflora resulted from their exposure to enrofloxacin. This work is consistent with earlier research by Dr. Jacobs-Reitsma. Jacobs-Reitsma, G-1459 at 7; G-315 at 2-3.

In another study, Newell and colleagues found that resistance to enrofloxacin and ciprofloxacin increased 7-8 times in C. jejuni recovered 48 hours after starting enrofloxacin treatment of the chickens in the study. McDermott, G-1465 at 4, 25 (unnumbered attachment).

Zhang, Luo, and colleagues at Ohio State University investigated the effect of dosing in evolution of enrofloxacin treatment, also finding that resistance emerged within 24-48 hours after treatment in both the group treated at 25 parts per million (ppm) enrofloxacin and the group treated at 50 ppm, and persisted after treatment ended. McDermott, G-1465 at 4; G-1800 at 2-3.³⁸ They did not find fluoroquinolone-resistant Campylobacter in the treated group of chickens before treatment or in a control group of chickens, id., which, as noted above, is an indication that it is the selection pressure of exposure to enrofloxacin that allows for the resistant Campylobacter to proliferate.

Research in live poultry demonstrates that the development of fluoroquinolone resistance on poultry farms is consistent with these controlled laboratory data. NARMs surveillance data from broiler carcass rinse samples that were analyzed to determine the prevalence of fluoroquinolone-resistant Campylobacter showed that 9.4%, 9.3%, 10.4%, and 17.6% of Campylobacter from broilers were resistant to ciprofloxacin in 1998, 1999, 2000, and 2001 respectively. Tollefson, G-1478 at 12. Dr. Catherine Logue's research shows that 8.8% of the Campylobacter isolates at one turkey processing plant she investigated were resistant to ciprofloxacin, as was a majority of the Campylobacter (65.2%) at a second plant. Logue, G-1464 at 6. Bayer witness Dr. Diane Newell described data on the prevalence of fluoroquinolone resistance in chicken at slaughter in a number of countries; the levels of resistance cited were 6% in Denmark (2001, C. jejuni only); 19% in Germany (1998); 32% in Japan (2001), and 99% in Spain (2000). Newell, B-1908 at 14.

One final note: cross-resistance in Campylobacter occurs throughout the fluoroquinolone drug class. Barrett, G-1453 at 2; Weber, G-1482 at 7-8. In other words, resistance to one fluoroquinolone may compromise the use of any fluoroquinolone to treat a particular bacterial infection. Tollefson, G-1478 at 4. Thus, Campylobacter resistant to enrofloxacin (the animal antibiotic) are cross-resistant to ciprofloxacin (the human antibiotic). Weber, G-1482 at 7-8. Campylobacter that are resistance to precursor compounds (quinolones), such as nalidixic acid, are also cross-resistant to fluoroquinolones. Barrett, G-1453 at 2; Tollefson, G-1478 at 9-10; see also Bayer Exceptions at 213 n. 55 ("in the case of Campylobacter, because of cross-resistance, "quinolone resistance' is essentially equivalent to "fluoroquinolone resistance.'").

In conclusion, I find that commercially produced chickens and turkeys in the United States are frequently colonized with Campylobacter, and that the colonization of Campylobacter persists until slaughter. I further find that the selection for fluoroquinolone-resistant Campylobacter occurs rapidly in poultry following initiation of fluoroquinolone treatment, and that fluoroquinolone-resistant Campylobacter persist until slaughter.

In contrast, I find the absence of fluoroquinolone treatment of poultry to be associated with a very low level of fluoroquinolone resistance in such untreated poultry, despite the fact that the actual mutation occurs spontaneously. This is important evidence linking the use of enrofloxacin in poultry to the emergence of resistant Campylobacter infections in poultry and exposure of humans to resistant Campylobacter.

C. Poultry consumption as a risk factor for human Campylobacter infection

1. Introduction

In addition to the data on persistent colonization of live poultry with susceptible Campylobacter and resistant Campylobacter, the presence of susceptible and resistant Campylobacter in and on broilers and turkeys presented for slaughter, and the frequency of contamination of poultry carcasses with susceptible and resistant Campylobacter, there is substantial other evidence supporting my determination that, in the United States, poultry consumption is a primary risk factor for human infections with Campylobacter, including fluoroquinolone-resistant Campylobacter . This evidence, described more fully in this section, comes from data on contamination of retail meat in the United States ; epidemiologic studies conducted in the United States and other countries; and microbiologic and molecular data linking poultry contamination with human Campylobacter infections.³⁹ Each of these additional groups of scientific evidence is discussed in turn.

I note at the outset of this discussion that there is no dispute that poultry is a source of Campylobacter infections in humans. See Bayer Exceptions at 37 n.12 ("Bayer has never claimed that poultry is not a source of Campylobacter"). Bayer does, however, challenge CVM's assertion that poultry is a predominant source of campylobacteriosis in the United States. Id. I find that the evidence supports CVM's position that poultry is a primary source in the United States of both susceptible and fluoroquinolone-resistant Campylobacter infections.

2. Retail meat studies

I find that Campylobacter contamination has been found on retail poultry products in every pertinent study in the record; that the presence of Campylobacter contamination is much more common on retail poultry than on other retail meat products; and that fluoroquinolone-resistant Campylobacter is now commonly found on retail chicken and turkey products. Significant investigations of retail poultry meat contamination include the studies discussed below.

In a study of 825 poultry and non-poultry meat samples randomly collected from retail stores in the Washington, D.C. area from June 1999 to July 2000, researchers from the University of Maryland examined 184 chicken carcasses and 172 turkey breasts, finding that the prevalence of Campylobacter in retail chicken was 70.7% and the prevalence in turkey was 14.5%. Meng, G-1466 at 2; G-727. In contrast, 1.7% of the pork samples and 0.5% of the beef samples were positive for Campylobacter. White, G-1484 at 3; G-727. Most (91%) of the 59 stores, from 4 different supermarket chains, had Campylobacter-contaminated chicken. Id. In the study, 722 Campylobacter isolates (595 from chicken, 112 from turkey, 11 from pork, and 4 from beef) were typed. About half of the isolates (53.6%) were identified as C. jejuni, 42.3% as C. coli, and 5.1% as other species. Meng, G-1466 at 3. C. coli was recovered more often from retail turkey samples than C. jejuni. Id. Eighteen chicken carcasses and 12 turkey breasts had more than one Campylobacter species present, and on two occasions three different species of Campylobacter were found in a single sample. Id.

More recently, the University of Maryland researchers evaluated the in vitro antimicrobial susceptibilities of 378 C. jejuni and C. coli isolates from 159 contaminated retail raw meat products (130 chicken, 25 turkey, 3 pork, 1 beef). Meng, G-1466 at 3-4; G-1778. They found 41% of the isolates were resistant to nalidixic acid and 35% were resistant to ciprofloxacin. Id.C. coli isolates had significantly higher resistance rates to ciprofloxacin than C. jejuni isolates. Id. Turkey isolates, from either Campylobacter species, showed significantly higher resistance rates to ciprofloxacin than did Campylobacter isolates from retail chickens. Id .

In 2002, NARMS began a pilot surveillance of retail meats to determine the prevalence of antimicrobial resistance among Salmonella, Campylobacter, E. coli, and enterococci isolated from samples of chicken, ground turkey, ground beef, and pork chops purchased from selected grocery stores in the United States . White, G-1484 at 3-4. As of November 2002, preliminary data indicated that 58% of 365 chicken breasts tested, 8% of 372 ground turkey samples, 3% of 373 ground beef samples, and 2% of 343 pork chop samples were positive for Campylobacter. White, G-1484 at 4.

Smith and colleagues conducted a survey of retail chicken products in Minnesota in 1996 as part of a larger study they conducted on quinolone-resistant⁴⁰ Campylobacter infections of humans. Smith, G-1473 at 5-6, 13; G-589 at 1, 5. They found Campylobacter on 88% of the 91 retail chicken products they tested, including C. jejuni (74%) and C. coli (21%), and both species on some products. Id . Ciprofloxacin-resistant Campylobacter (MIC > 32 μg/mL) was isolated from 20% of these poultry products. Id.

There are several other retail meat studies in the record, which CVM witness Dr. David G. White described. See White, G-1484 at 3-8. These and other data in the record establish that a substantial proportion of the raw retail chicken products in the United States are contaminated with Campylobacter in general and also with fluoroquinolone-resistant Campylobacter.⁴¹

Bayer argues that, even if these data establish the presence of Campylobacter on poultry, these Campylobacter are for various reasons not capable of causing human illness, either because they are the wrong strains of Campylobacter or because they are present in insufficient amounts to cause human illness. I discuss Bayer's challenges to the molecular and genetic evidence linking poultry contamination and human illness in the next section. I address below Bayer's dose-response argument, which is also a substantial part of its challenge to CVM's risk assessment (see section III.D.4 below).

a. Dose-response

In the context of its challenge to the retail meat studies and elsewhere in its exceptions, Bayer argues that evidence concerning the presence of Campylobacter on retail poultry meat is insufficient to show a risk of harm without evidence that the amount of bacterial contamination present is sufficient to cause illness. See, e.g., Bayer Exceptions at 185. I disagree.⁴²

First, the evidence in the record linking consumption of poultry and human campylobacteriosis is sufficient without calculating the precise amount of bacteria (which the participants refer to as "bacterial load") found on particular products, and without knowing exactly how much Campylobacter a person must consume to become ill. As described above, there is abundant evidence in the record establishing that Campylobacter and fluoroquinolone-resistant Campylobacter are found on poultry carcasses and retail meat. See, e.g., White, G-1484 at 2-3, 4, 7; Meng, G-1466 at 3. The epidemiologic studies described below make clear that poultry consumption is a primary risk factor for sporadic Campylobacter infections in the general population in the United States. Furthermore, the molecular data support the epidemiologic data, because these genetic and other "fingerprinting" studies demonstrate that bacterial strains found in retail poultry meats are also isolated from human patients. These data support a finding that, with respect to Campylobacter, the bacterial load to which people are exposed when they consume or prepare poultry is sufficient to make at least some exposed people sick at least some of the time, such that, as discussed above, public health experts estimate that there are more than a million cases of campylobacteriosis each year in the United States, a large proportion of which are associated with poultry and chicken handling and consumption.

In addition, although in general the retail meat studies do not quantify bacterial load on the products tested, there are FSIS data on the prevalence and levels of bacteria (including Campylobacter) on turkey and chicken carcasses in the United States; these data indicate that broilers and turkeys carry a higher carcass and ground product load of Campylobacter than do other food animal carcasses/products. G-651; G-652; see also G-1656 (1987 report of small investigation in England that found high bacterial load on 82 chickens purchased at 11 retailers).

Finally, I find that the very limited research in the record on the infective dose, i.e., the amount of bacteria needed to make someone ill, supports a finding that the dose needed to cause illness can be very low, although the precise dose-response⁴³ relationship between exposure to Campylobacter and human illness has not been established.

The participants stipulated that the risk that a given meal will cause campylobacteriosis depends at least in part on the number of colony-forming units (CFUs)⁴⁴ of Campylobacter ingested. Revised Joint Stipulation 27. However, this is not the same as stipulating that there is a dose at which no effect can occur in at least some exposed people.⁴⁵

There are only two studies in the record investigating the infective dose of Campylobacter. One is a case report, published in 1981, about an experiment in which the researcher (Robinson) ingested one dose of 500 CFUs of C. jejuni and then became ill. G-1816. The second is a study by Black in which 111 healthy young adult volunteers were exposed to one of two different strains of C. jejuni in a range of doses from 800 CFUs to 2 x 10 9 CFUs. G-67; see Tauxe, G-1475 at 5. Black found that rates of infection increased with dose, "but development of illness did not show a clear dose relationship." G-67 at 1. One strain was more likely to cause illness and caused more severe illness. Id. One person in the Black study developed illness at the lowest dose administered in the study (800 CFUs). G-67 at 4. Thus, neither the Black nor Robinson study identifies the minimal dose needed to cause illness, although they suggest it is lower than the lowest doses ingested in these studies. CVM witness Dr. Robert Tauxe testified that in his expert opinion, based on data from a study in the United Kingdom (U.K.) that estimated a thousand to a million Campylobacter per chicken (G-1656), "a drop of raw chicken juice would often include an infectious dose of 500 organisms [i.e., CFUs]." G-1475 at 10. Dr. Tauxe also testified about the ease of cross-contamination of other foods with Campylobacter from raw poultry through improperly cleaned cutting boards or other kitchen surfaces and utensils. Id. This evidence suggests that even minimal spread of contaminated "chicken juice" can result in illness.⁴⁶

In sum, the record shows that illness can occur at very low levels of exposure to Campylobacter. I find that there is no scientific justification for disregarding the retail meat studies because they do not provide a measure of bacterial load. The retail meat studies show that the contamination of poultry meat persists to and after the point of purchase, providing further evidence in the link between fluoroquinolone use in poultry and fluoroquinolone-resistant Campylobacter infections in humans. We know from these studies that, in different areas of the country and over a range of recent years, all researchers investigating retail meat contamination have found that a large proportion of retail poultry products is contaminated with Campylobacter. Moreover, recent studies consistently have shown that a large proportion of the products is contaminated with Campylobacter that are resistant to fluoroquinolones. This is important evidence linking human infections to poultry consumption. In the section above, I described evidence that demonstrated how common Campylobacter colonization of poultry is and how that contamination persists until slaughter. The evidence described in this section establishes that sufficient contamination persists on poultry carcasses and retail poultry meat products at the point of consumer purchase to be a hazard to human health.

The next links in the chain, discussed in sections III.C.3 and 4 below, are the epidemiologic and microbiologic studies showing that handling raw poultry, eating undercooked chicken and turkey meat, and cross-contamination from raw poultry to other food products, are major risk factors for campylobacteriosis.

3. Epidemiologic evidence

a. Introduction

Several case-control studies from the United States and elsewhere have shown that the risk of Campylobacter infection is significantly elevated with respect to: consumption of poultry generally; poultry consumption in restaurants; consumption of undercooked or raw poultry; handling of raw chicken; and failure to clean food preparation or cutting board surfaces. The association between poultry and Campylobacter infections in humans is generally consistent across studies, despite broad differences in size, methodology, and sample population. Angulo, G-1452 at 89-90 (Att. 3) (prior to the FoodNet study described in his testimony and below, "at least 14 previous epidemiologic investigations of sporadic Campylobacter infections implicate exposure to poultry as a major risk factor.") Estimates of the proportion of human campylobacteriosis cases attributable to poultry range from 28%, id. at 10, 101, to 70%, Endtz, G-1457 at 4.

b. United States case-control studies

Early case-control research from the 1980s in the United States linked chicken consumption and Campylobacter infections soon after identification of campylobacteriosis as a common human enteric disease. Harris and colleagues identified 218 cases of confirmed C. jejuni or C.coli infections diagnosed through a health maintenance organization in Washington State and matched them to 526 controls by age and month of interview. G-268. They found that consumption of chicken and Cornish game hen was associated with more than a double risk of infection, and that consumption of raw chicken was even more strongly associated with illness. Id . at 4.⁴⁷ The researchers estimated that 48% of the cases would not have occurred had chicken not been consumed. G-268 at 4. The Harris study also found processed turkey meat was significantly associated with illness. G-268 at 4; Tauxe, G-1475 at 9.

In a small study of risk factors for C. jejuni enteritis among college students in Georgia, Deming and colleagues found, comparing 45 cases to 45 controls, that eating fully cooked chicken, eating chicken reported to be raw or undercooked, and contact with a cat or kitten were all significantly associated with illness. G-162. Those data indicated that 66.7% (95% CI 20.2-86.1) of cases were attributed to eating chicken. Id . at 6; see G-953 at 53 (calculating percent attributed to chicken based on reported data). See also G-299 and B-412 (small studies from Colorado in 1981 and 1982 linking raw or undercooked chicken and illness); G-564 (small study in Iowa of campylobacteriosis occurring from April 1982 to March 1983 found no link between infection and chicken consumption, but noted that "large numbers of chicken carcasses at retail stores were contaminated with C. jejuni, the seasonal distribution of disease onset and percentages of chicken carcasses that were positive was similar, and serotyping did not differentiate patients' strains from chicken strains of C. jejuni. Thus, in our study, poultry remains a possible, but unproved, source of human infection." Id . at 4; G-1644 at 10 (review article).

The largest case-control study of sporadic Campylobacter infections in the United States was conducted in the FoodNet sites in 1998 and 1999. Angulo, G-1452 at 9-10 and 79-107 (Att. 3). The study, by Friedman and colleagues, matched 1316 cases with culture-confirmed Campylobacter infections to 1316 controls of the same age. Id. Cases and controls were asked about foreign travel, food and water exposures, and food handling practices in the seven days before the case became ill. Id. The 164 cases (13%) that reported travel outside of the United States in the seven days prior to onset of illness were excluded, along with their matched controls, from the final statistical analysis performed to identify risk factors for domestically acquired Campylobacter infections. Id.

In a statistical analysis that included a number of risk factors associated with campylobacteriosis, Friedman found that cases were more than twice as likely to have eaten chicken or turkey in a restaurant than were controls. Angulo, G-1452 at 10.⁴⁸ Friedman calculated that the population attributable fraction⁴⁹ of illness associated with chicken prepared at a restaurant was 24% (95% CI 17%-30%), and the population attributable fraction of illness associated with turkey prepared at a restaurant was 4% (95% CI 1%-6%). Angulo, G-1452 at 10, 101 (Att. 3); G-1488.⁵⁰ In other words, in their analysis, 24% of the campylobacteriosis cases in the study population may be attributable to eating chicken in restaurants and 4% to eating turkey in restaurants.

The Friedman analysis found no increased risk of illness for cases who reported having eaten poultry at home; in that analysis, controls were more likely to report having eaten chicken or turkey prepared at home. Angulo, G-1452 at 90, 101 (Att. 3).⁵¹

As the authors acknowledge, there are limitations to the Friedman study. Angulo, G-1452 at 93-94 (Att. 3). In addition to the potential for bias inherent in observational case-control research, this investigation was a screening study that encompassed hundreds of independent and overlapping exposure factors, some of which were included in the final multivariate analysis (e.g., "Ate chicken prepared at a restaurant," "Ate undercooked or pink chicken," "Ate fried chicken"). Id . at 101. Because of the large number of variables analyzed in the study, many of which were interrelated, see Angulo, G-1452 at 98 (Att. 3), the relationship between particular risk factors and the outcome of interest (campylobacteriosis) is best analyzed in the context of the entire body of research on risk factors for Campylobacter infection.

In light of these limitations, it is noteworthy that the Friedman study is consistent with other studies that also identified Campylobacter risk associated with poultry consumption in restaurants. Indeed, this consistency with other, smaller studies may be more meaningful than the actual values estimated through the statistical model.

Bayer argues that the findings of the Friedman study show that "some factor other than poultry consumption must be affecting the risk of infection with Campylobacter." Bayer Exceptions at 184, 196. Bayer suggests that "[r]estaurant workers ... or veal ... could easily be additional sources of restaurant cross contamination of many other foods. CVM has not shown otherwise." Id . at 184 (citations omitted).

I do not agree. First, CVM does not have to disprove, and in fact does not contest, that there are other sources of Campylobacter infection. See Revised Joint Stipulation at 32 ("[s]ources of Campylobacter infection other than poultry, such as domestic pets, are known"). The burden on CVM in this proceeding is to show that poultry is a risk factor for fluoroquinolone-resistant Campylobacter infection. As discussed in this Final Decision, CVM' s evidence shows that poultry is a primary risk factor with respect to both fluoroquinolone-resistant and fluoroquinolone-susceptible Campylobacter.

Second, Bayer does not provide sufficient evidence to support its allegations that restaurant workers, veal, or flies or rodents are plausible sources of sporadic Campylobacter infections in humans. Exhibit G-22, cited by Bayer in support of its "veal" (and fly and rodent) claim, is a review article; neither the article nor the underlying research support Bayer ' s claim. As support for the "restaurant worker" claim, Bayer cites to a statement in an attachment⁵² to the stricken written direct testimony of Dr. Anthony Cox, which in turn cites the testimony of CVM witness Dr. Frederick Angulo. I find that Dr. Angulo' s full testimony and other evidence in the record do not support Dr. Cox' s interpretation.⁵³ Thus, even if Dr. Cox' s testimony were not stricken, I would find Bayer's argument with respect to veal and vermin entitled to little weight, and the evidence on food handlers simply unreliable. This testimony plainly does not refute the evidence that poultry, and cross-contamination due to poultry contamination, are a primary source of Campylobacter infections in the United States .

Finally, because of the way the study was designed, the Friedman analysis provides information about risk associated with poultry consumption in restaurants, as explained above, but it cannot support any conclusions about the independent risks posed by poultry, other meats and foods, food handlers and handling practices, or by restaurants. Furthermore, there is plenty of evidence in this record demonstrating an association between consumption of poultry and acquiring campylobacteriosis; the same cannot be said about data linking eating in a restaurant with the illness. While there may be some lower risk of campylobacteriosis associated with consuming other meats in a restaurant setting, see Angulo, G-1452 at 10-11 and 89, 92 (Att. 3), most of the evidence in the record linking food consumption and sporadic campylobacteriosis involves consumption of chicken and turkey and probable cross-contamination of other foods with bacteria originating from raw poultry. Angulo, G-1452 at 12-13; Tauxe, G-1475 at 7-10.

In a smaller recent case-control study, Effler and colleagues investigated indigenous exposures contributing to the high incidence of sporadic C. jejuni infections in Hawaii , which has the highest rate of C. jejuni infections in the United States . G-185 at 1. The study involved 211 cases with confirmed Campylobacter infection, each matched to one age-and telephone-exchange matched control. Effler found that people who ate chicken prepared by a commercial food establishment in the seven days before case illness onset were just under twice as likely to become ill as controls (AOR 1.8; 95% CI 1.1-2.9).⁵⁴

In sum, I find that the research conducted in the United States , described in this section, provides solid and reliable evidence that the consumption of poultry is a primary risk factor for campylobacteriosis. Research from other nations supporting the conclusions of the United States studies is discussed below.

c. Non-U.S. studies

European studies also support the link between chicken consumption and risk of campylobacteriosis. I find that these studies provide information that is useful and relevant to the United States . Tr. at 408; Endtz, G-1457 at 7 ("Twenty-five years of study of the epidemiology of Campylobacter infections in the U.S. and Europe has not come up with data that refute the hypothesis that epidemiology of Campylobacter in the two continents is in essence very comparable. Therefore, data from outside the U.S. include valuable information that may be extrapolated to the U.S. situation."). Studies of risk factors for Campylobacter infections are available from Denmark , the Netherlands , Norway , Sweden , Switzerland , and the United Kingdom . See Wegener, G-1483 at 14 (table of case-control studies from 1979-1998). Consumption of poultry is identified as a risk factor in studies in Sweden, G-602 at 1; the United Kingdom, G-1686 at 1; Switzerland, G-1718 at 1; Norway, G-334 at 1; and the Netherlands, G-474. In Denmark , Neimann identified eating undercooked chicken as a risk factor for illness, Wegener, G-1483 at 13, and in England , Rodrigues identified eating chicken in a restaurant as a risk factor, G-1711 at 2.

Similar findings can be seen in studies conducted in Canada and New Zealand . Michaud and colleagues ( Canada ) found in a case control study conducted in Canada in 2000-2001 that eating undercooked poultry and failing to clean kitchen surfaces were each risk factors for campylobacteriosis. G-1681; Tauxe, G-1475 at 9. A study in New Zealand found that eating undercooked poultry was a risk factor for illness, as was eating chicken in a restaurant, G-182, while a second New Zealand study found that eating undercooked chicken, eating poultry at a barbeque (a risk the authors hypothesized may be associated with inadequate cooking, lack of refrigeration, or cross-contamination), and eating poultry at a friend's house (a risk the authors suggested might be associated with catering to larger numbers than usual) were risk factors for infection, G-307 at 3.

Thus, I find, with respect to the record evidence concerning epidemiologic studies conducted in the United States and other developed nations to determine risk factors for sporadic Campylobacter infections, that, "[a]lthough these studies differed in location, technique, and sample size, they consistently indicate several dominant sources of infection, including contact with and consumption of chicken and turkey." Angulo, G-1452 at 9.

d. Intervention studies

I find that further epidemiologic evidence of the link between Campylobacter and poultry consumption is found in studies of the impact on Campylobacter infections of changes in a population's poultry consumption, referred to by the participants as "intervention studies." Wegener, G-1483 at 18.

One such situation occurred in Belgium in 1999, when domestic poultry and eggs were taken off the market for a month because dioxin had been detected in animal feed (imported poultry and other meat products were still available to consumers). Id. The incidence of human Campylobacter infections dropped in Belgium almost 40% in the month that domestic poultry was unavailable (based on a model generated from data for the period from 1994 to 1998). Endtz, G-1457 at 4; Wegener, G-1483 at 18; G-672. Researchers hypothesized that the fact that 41% of poultry sold in Belgium is imported (and remained available to consumers) could explain in part the cases of campylobacteriosis that did occur during that period. Id.

Similarly, Iceland experienced an increase in Campylobacter infections from 1997 to 1999, a period of time that coincided with the introduction of fresh, rather than the traditionally available frozen, chicken products on the market. Wegener, G-1483 at 18. After the country imposed stringent control measures to test poultry for Campylobacter at slaughter and to process and market contaminated poultry meat differently from uncontaminated meat, incidence of domestically acquired campylobacteriosis in Iceland was reduced by about 70%. Wegener, G-1483 at 19. Norway has implemented a similar program and early results showed after 39 weeks an almost 50% reduction in domestically acquired campylobacteriosis. Id.

e. Fluoroquinolone-resistant Campylobacter infections

The epidemiologic studies I have described thus far identified risk factors for acquiring Campylobacter infections, without consideration of the susceptibility or resistance of the bacteria to fluoroquinolones. However, the record demonstrates, and I find, that there are no significant biologic reasons that transmission of fluoroquinolone-resistant Campylobacter infections from animals to humans is different from transmission of fluoroquinolone-susceptible infections. Wegener, G-1483 at 20. As a result, it can be expected that when resistance to fluoroquinolones emerges in Campylobacter in animals, resistant Campylobacter will be transmitted to humans, id., and investigations have shown temporally that this in fact occurs, id. at 21.

Not surprisingly, then, research focused specifically on identifying risk factors for fluoroquinolone-resistant Campylobacter infections confirm that consumption of poultry is a risk factor. Using the FoodNet Campylobacter case-control data, Kassenborg and colleagues evaluated risk factors associated with fluoroquinolone-resistant Campylobacter infections. They interviewed 646 of 858 (75%) cases for whom information on resistance to fluoroquinolones was known. Kassenborg, G-1460 at 6; G-337.⁵⁵ Of these 646 cases, 64 had infections that were resistant to fluoroquinolones and 582 had infections that were sensitive to fluoroquinolones. Id .

Although Kassenborg found that some of the cases with fluoroquinolone-resistant Campylobacter infections had likely become infected outside of the United States, I find it noteworthy that a majority of the 64 cases with fluoroquinolone-resistant infections (37 out of 64, or 58%) had infections that were domestically acquired (in other words, the cases had no history of travel outside of the United States in the week before they became ill).⁵⁶ Furthermore, domestically acquired fluoroquinolone-resistant Campylobacter infections were reported in all of the FoodNet surveillance sites. Kassenborg, G-1460 at 7. These data are consistent with the NARMS data, described below, indicating that an increasing proportion of human Campylobacter infections are resistant to fluoroquinolones and refuting Bayer' s arguments (see section III.D.2. below) that these cases can be attributed to Campylobacter infections acquired outside of the United States. Together with the data from retail food sampling demonstrating the presence of fluoroquinolone-resistant Campylobacter on poultry products in the United States , this research supports a conclusion that poultry is the dominant source of domestically acquired fluoroquinolone-resistant Campylobacter infections in the United States . Id. at 9.

In a statistical analysis that incorporated a number of risk factors, Kassenborg found that the 37 cases with domestically acquired fluoroquinolone-resistant infections were ten times more likely to have eaten chicken or turkey at a commercial establishment than were their age-matched controls (95% CI 1.3-78). Kassenborg, G-1460 at 8; G-337 at 15.⁵⁷

Despite certain methodologic and statistical limitations, such as the high degree of correlation among certain of the study variables (e.g., 75% of cases reported "eating in a non-fast food restaurant" and 55% reported "eating chicken or turkey at a commercial establishment," G-337 at 15) and the limitations inherent in any questionnaire-based case-control research, I find that the Kassenborg study provides valuable information about domestically acquired fluoroquinolone-resistant Campylobacter infections.

f. Temporal data on human fluoroquinolone-resistant Campylobacter infections

I also find that data from several countries, including the United States, indicate that a rise in human Campylobacter infections that are resistant to fluoroquinolones has consistently followed the introduction of enrofloxacin in poultry production in that country. As noted in the discussion of epidemiologic evidence in section II.D.2.c above, an indication that an exposure precedes the outcome of interest is consistent with a causal association.

(i) Data from the United States

Veterinary use of sarafloxacin and enrofloxacin was approved in the United States in August 1995 and October 1996, respectively. Revised Joint Stipulations 39, 47. If there is evidence that Campylobacter isolates from human stool samples had higher levels of resistance to fluoroquinolones after approval than they had before approval, and that the level of resistance continued to increase following approval, this evidence would support a finding that the use of enrofloxacin in poultry has resulted in increased resistance to fluoroquinolones in human Campylobacter infections.

As described below, the participants each provided a set of studies intended to show what the pre-approval "baseline" of fluoroquinolone resistance was among C. jejuni and C. coli in the United States. I find that fluoroquinolone resistance was very low (i.e., less than 5% of human Campylobacter isolates) prior approval and use of enrofloxacin in poultry in the United States. In so finding, I disagree with Bayer that the evidence shows that as early as 1995 fluoroquinolone resistance in Campylobacter was as high as 20%. I also find that the longer enrofloxacin has been in use, in the United States and elsewhere, the more resistance to fluoroquinolones has been found in human Campylobacter isolates.

At the outset, it is important to understand the role of nalidixic acid with respect to fluoroquinolone resistance in Campylobacter. Nalidixic acid is a precursor to fluoroquinolones, Barrett, G-1453 at 2, and fluoroquinolone-resistant Campylobacter are typically also resistant to nalidixic acid. Id. Thus, data on resistance to nalidixic acid are relevant to understanding how common fluoroquinolone resistance was prior to the approval of enrofloxacin and sarafloxacin. Fortuitously, these data are available because, throughout the 1980s, resistance to nalidixic acid was used in the laboratory to distinguish C. jejuni and C. coli, which were almost universally susceptible to nalidixic acid, from C. lari, which is not (for reasons that are not germane to this proceeding). Barrett, G-1453 at 2-3. Published research using resistance to nalidixic acid to distinguish among Campylobacter species found in human stool isolates shows that, before the introduction of enrofloxacin, C. jejuni and C. coli were almost entirely susceptible to nalidixic acid, and by implication, also susceptible to fluoroquinolones. In one such study, Barrett and colleagues reported in 1988 that only 2 of 42 C. jejuni isolates, and 0 out of 25 C. coli isolates (from human stool samples) were resistant to nalidixic acid, while all (23 out of 23) C. lari isolates were resistant. Id. at 3; G-1609 at 5.⁵⁸

In Minnesota, Smith and colleagues observed an increase in quinolone-resistant⁵⁹ Campylobacter infections in humans from 1.3% in 1992 to 10.2% in 1998. Smith, G-1473 at 7; G-589 at 6. Part of that increase can be explained by foreign travel and quinolone use by the patients prior to collection of stool specimens. See Revised Joint Stipulations 8, 9. However, in an analysis of data from 1996-1998 that excluded patients with a history of foreign travel, Smith found that there was still a statistically significant increase in resistance to quinolones in domestically acquired C. jejuni infections between 1996 and 1998. Smith, G-1473 at 12. Smith estimated that only a maximum of 15% of quinolone-resistant Campylobacter infections could have been due to prior quinolone therapy in the patient. G-1473 at 15; G-589 at 6.⁶⁰

In 1989, Tenover and colleagues analyzed 332 C. jejuni isolates and found only one to be resistant to ciprofloxacin. Barrett, G-1453 at 3. The resistant isolate later proved to be C. lari (and as a result the resistance can be presumed to be a characteristic of the bacteria rather than a result of exposure to fluoroquinolones). Barrett, G-1453 at 3; Nachamkin, G-1470 at 6. Dr. Barrett testified that the 1989 data by Tenover is appropriately considered a "baseline" from which to evaluate the later emergence of resistance in C. jejuni and C. coli. Barrett, G-1453 at 3.

Nachamkin and colleagues tested 132 C. jejuni isolates from patients with gastroenteritis at the University of Pennsylvania Medical Center between 1982 and 1992. Nachamkin, G-1470 at 6. During this ten-year period, none of the isolates was resistant to ciprofloxacin. In a follow-up study, Nachamkin found that among 297 C. jejuni isolates collected from patients (most of whom were outpatient) between 1995 and 2001 within the University of Pennsylvania Health System, 8.3% of the isolates were resistant to ciprofloxacin in 1996 and 40.5% were resistant in 2001. Nachamkin, G-1470 at 6. All but one of the resistant isolates had a ciprofloxacin MIC ≥ 32 μg/mL. Id.

In sum, I agree with the Initial Decision's finding that "[i]t is not clear what was the exact pre-approval level of fluoroquinolone resistance in the United States. Nevertheless, those levels appear significantly higher post-approval as compared to preapproval." Initial Decision at 52. Indeed, I would state this even more strongly: I find that the weight of evidence in the record establishes that post-approval levels of quinolone-resistance in human Campylobacter isolates are substantially higher than pre-approval levels of such resistance.

In so finding, I disagree with Bayer that the weight of the evidence is to the contrary. Bayer Exceptions at 149. I also find that Bayer's additional challenges to research relied on by CVM with respect to this issue are not based on evidence deserving of much weight.

First, Bayer cites to research by Kiehlbach and colleagues comparing Campylobacter isolation on selective media to that obtained by filtration. B-39. Fecal specimens collected between 1992 and 1995 were cultured, and 97 Campylobacter isolates obtained. Id. at 2-3. Forty of these were identified as C. jejuni and three as C. coli. The report notes that 88% of the C. jejuni isolates were susceptible to ciprofloxacin. Id. at 3. It does not, however, identify how susceptibility was defined and it does not define the proportion that was resistant, and I find that it is inappropriate to assume, as Bayer does, Bayer Exceptions at 149-150, that a reported susceptibility of 88% means a resistance rate of 12%.⁶¹

Exhibit B-67, which Bayer also cites, is an abstract describing 181 Campylobacter isolates collected during an outbreak of enteritis at a nursing home in New York in 1993, 6 (3.3%) of which were found to be resistant to nalidixic acid. B-67; DeGroot, A-200 at 6. In this outbreak, the percentage of infections that was resistant was less than 5%, so to the extent the abstract is relevant (since it concerns an outbreak, not sporadic infections), these data are consistent with my findings about baseline levels of quinolone resistance.

Finally, Bayer cites a draft paper by Nachamkin and colleagues (G-1517) reporting on an increase in fluoroquinolone resistance in Campylobacter isolates from the University of Pennsylvania Health System. Bayer Exceptions at 150. That study, which looked at 297 case isolates collected from 1995 to 2001, reported an increase over time from 8.3% (1996) to 40.5% (2001). G-1517 at 4-5. The draft does not report the proportion of isolates resistant for the other years covered by the study (1997 to 2000), but indicates them graphically at Figure 1. G-1517 at 11. Bayer cites this figure because it indicates about 20% resistance for 1995. There is no information in this study or elsewhere in the record that allows for an understanding of why the 1995 isolates for this one year within this population were elevated, but a number of epidemiologic variables may have made this study population unrepresentative of the general population. Therefore, I decline Bayer's invitation to give this one data point extraordinary weight, as it is clearly out of line with Nachamkin's other data and the other evidence on this issue. E.g., G-589; G-440; Barrett, G-1453 at 3, G-1609.⁶²

I conclude that the totality of Dr. Nachamkin's research shows that from 1982 to 1992, there was no resistance to ciprofloxacin in Campylobacter isolates collected in the University of Pennsylvania Health System; that in 1996, the proportion that was resistant was 8.3%, and that in 2001 the proportion that was resistant was 40.5%. G-440; G-1517. I also find that, as described in this section, there is evidence in the record, in particular the data about which Dr. Barrett and Dr. Nachamkin testified, that fluoroquinolone resistance rates in the United States were low before August 1995, when fluoroquinolones were first approved for veterinary use, and that they have increased significantly since fluoroquinolones were approved for veterinary use in the United States.

I also find that the NARMS and other data show that the proportion of human Campylobacter isolates that was resistant to ciprofloxacin increased significantly in the period following approval of fluoroquinolones for veterinary use. NARMS data show that the percentage of Campylobacter isolates that was resistant to ciprofloxacin was 13% (28/217) in 1997, the first year of such testing; 14% (48/345) in 1998, 18% (58/319) in 1999, 14% (46/324) in 2000, and 19% (75/387) in 2001. Angulo, G-1452 at 8, 74-78 (Att. 2). The NARMS analysis found a modest but statistically significant increase over the time period from 1997 to 2001. Angulo, G-1452 at 7-9, 74-78 (Att. 2); Molbak, G-1468 at 8. The proportion of human Campylobacter isolates that was resistant to ciprofloxacin (adjusting for site variation and age) was 2.5 times higher in 2001 (95% CI 1.4-4.4) than it was in 1997. Angulo, G-1452 at 8-9, 74-78 (Att. 2). These data parallel the findings from Minnesota in which resistance among human Campylobacter isolates rose from 1.3% in 1992 to 10.2% in 1998. G-589 at 6.

Bayer raises several challenges to these temporal data. First, Bayer argues that the human NARMS data for Campylobacter are not nationally representative. Bayer Exceptions at 156-160. Bayer's specific arguments are that the sampling scheme does not produce a nationally representative sample, because only one sample per month per state is collected, and that data from Connecticut skew the analysis because of "an unexplained one-year spike in resistance from Connecticut." Bayer Exceptions at 158; see Molbak, G-1468 at 8 (in 1999, the number of resistant isolates from Connecticut was high).

While no surveillance system is without limitations, see Tr. at 358-359, I find that the NARMS data provide reliable information about the prevalence of fluoroquinolone-resistance in Campylobacter infections in the United States. Because the sampling scheme has not changed over time, any bias will affect all years. As a result, a statistically significant increase in prevalence over time is sufficiently robust, even if the exact figures are not perfectly correct. Tr. at 437. Furthermore, CVM witness Dr. Frederick Angulo testified that CDC had investigated the sampling basis of NARMS and that as a result he was "confident that the prevalence that we're measuring in NARMS is a close approximation of the national prevalence of fluoroquinolone-resistant Campylobacter." Id. at 438; see also Tr. at 135.

Bayer argues that, because there is seasonal variability in some states with respect to infections with Campylobacter and resistant Campylobacter, see Tr. at 124-128, 381-83, including only one isolate per week per participating state laboratory skews the data toward resistance. Bayer Exceptions at 157-158. Dr. Angulo's testimony recognized that there are variations from month to month on the proportion of Campylobacter infections that is resistant to fluoroquinolones; the proportion varies from state to state and in some, but not all, states it can be seasonal, although in general, there is seasonality across FoodNet sites. Tr. at 381-82. However, there is evidence in the record that CDC periodically evaluates the FoodNet surveillance system to confirm the "generalizability," or external validity, of the data it generates. Tr. at 311, 315, 320-325. Inasmuch as NARMS operates under the general umbrella of FoodNet, it is likely that its sampling scheme produces data that likewise can be generalized to the general population. Tr. at 358. Furthermore, even with respect to Minnesota, a state in which seasonal variation is apparent, Tr. at 382, AHI witness Dr. Bradley DeGroot testified that any seasonal bias "explains only a small proportion of the number of resistant isolates submitted by Minnesota to the Human NARMS program, beyond what can be expected based on overall resistance measured for the state," DeGroot, A-200 at 24. Dr. DeGroot testified that he believed that the seasonal selection bias inflated estimates from all contributing sites. I find that any bias cr