Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 1 of 78 PageID: TAB A Second Declaration of Loren Laine, M.D.

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1 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 1 of 78 PageID: 1898 TAB A Second Declaration of Loren Laine, M.D.

2 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 2 of 78 PageID: 1899 UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY UNITED STATES OF AMERICA, Plaintiff, v. BAYER CORPORATION, Civ. Action No SECOND DECLARATION OF LOREN LAINE, M.D. Defendant. I, Loren Laine, M.D., hereby declare as follows: I have reviewed the defendant s brief filed on December 23, 2014 and the four accompanying expert declarations along with the recent expert depositions. I can state unequivocally that the experts have not provided competent and reliable scientific evidence to substantiate claims that Phillips Colon Health (PCH) prevents, cures, or treats constipation, diarrhea, or gas and bloating or claims that PCH helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. In this report, I provide detailed point-by-point responses to specific comments which illustrate the key points from each of the expert declarations. Prior to the point-by-point responses, I provide a summary of the main issues raised in the declarations. The items in the summary are explained and referenced in much greater detail in the point-by-point responses.

3 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 3 of 78 PageID: 1900 SUMMARY 1) Standard-of-care criteria for physicians in clinical practice differ greatly from criteria for competent and reliable scientific evidence to substantiate a claim. Bayer s experts repeatedly focus on criteria for standard of care (i.e., what is needed for physicians treating patients in practice) rather than the criteria for competent and reliable scientific evidence for claims that a product is effective. I understand that use of probiotics is within the standard of care for physicians caring for patients in practice. As a physician, I know of no standard-of-care requirement that competent and reliable scientific evidence must be available for decisions made by physicians in clinical practice. Physicians in practice must make clinical decisions each day on the basis of currently available data even when studies that yield accurate and reliable results (and thus provide competent and reliable scientific evidence) are not available. In contrast, a decision to accept a claim is not required and presumably would not be made in the absence of competent and reliable scientific evidence. 2) High-quality randomized clinical trials are practical and ethical and are the appropriate method to yield accurate and reliable results. The repeated suggestion that randomized, controlled trials (RCTs) of a probiotic for the PCH claims at issue are not practical, feasible, or ethical is incorrect and is belied by the numerous such trials produced in these proceedings and by the numerous double-blind, placebo-controlled randomized trials by Bayer s own expert, 2

4 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 4 of 78 PageID: 1901 Dr. Merenstein. Such trials would not require thousands of patients followed for many years as suggested, but approximately subjects followed for weeks to months. Since a probiotic is not taken by most people in the U.S. and is not a standard-of-care requirement for adults with or without GI symptoms, a suggestion that it is unethical to employ a placebo probiotic is unfounded. In his deposition, Dr. Merenstein agrees that a placebo-controlled trial of a probiotic does not raise ethical concerns. The expert declarations indicate disagreement with my criteria for competent and reliable scientific evidence regarding the PCH claims. In contrast, publications, reports, and citations from Drs. Fennerty, Merenstein, and Blumberg support my position, stressing the importance and primacy of high-quality RCTs in evaluating the clinical efficacy of a supplement such as PCH. Publications from Dr. Fennerty and evidence-based experts cited by Dr. Blumberg indicate that double-blind, placebocontrolled randomized trials are needed to produce the accurate and reliable results that constitute competent and reliable scientific evidence. Dr. Merenstein s publications repeatedly make the case for high-quality research and controlled clinical trials and bemoan the fact that many products present themselves as a panacea while lacking patient-oriented outcome data. Drs. Fennerty and Blumberg have previously applied standards similar to mine in evaluating supplements and food products and found, even in the presence of numerous positive RCTs, that the evidence did not support efficacy. Dr. Fennerty s own publication assessing the efficacy of 3

5 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 5 of 78 PageID: 1902 supplements and medications states that Grade A recommendations are the only reliable grade for recommending a therapy, 1 and he agrees that the available evidence for the PCH claims does not satisfy his published criteria for reliable evidence. Thus, as experts in these proceedings, Drs. Fennerty, Merenstein, and Blumberg disagree with me regarding the need for high-quality RCTs to substantiate the PCH claims at issue. In contrast, as authors, their prior articles and reports indicate agreement with me regarding the need for high-quality RCTs. 3) In vitro and animal studies establish biological plausibility but don t provide competent and reliable scientific evidence of benefit for PCH in constipation, diarrhea, or gas and bloating. Pre-clinical work (e.g., in vitro, animal studies) on probiotics provides biologic plausibility for GI tract effect, but biological plausibility merely establishes that it is reasonable to study a probiotic product in clinical trials. Long lists of possible mechanisms by which probiotics and PCH may exert effects in the GI tract are provided by the experts and in cited articles. Dr. Merenstein, when discussing mechanisms underlying probiotic effects in his deposition (p ), agrees that the list of mechanisms he provides are potential mechanisms from these species, and that precise mechanisms are not known. Dr. Benson, in his deposition, admits that science has not progressed to the point where it can identify which of these mechanisms may cause occasional gas and bloating, occasional diarrhea or occasional constipation in an otherwise normal healthy person (p. 114). Dr. Fennerty, in his deposition, states the exact mechanism of the many mechanisms by which probiotics 4

6 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 6 of 78 PageID: 1903 affect the human gut and how that correlates directly to a specific symptom is unknown (p.147). Similarities among different strains in mechanisms or genetic content in no way indicate that the strains are beneficial for constipation, diarrhea, or gas and bloating because clinical benefit in these symptoms and a precise mechanism for such a clinical benefit is not established. Until and unless we have documentation that a strain of a bacteria benefits constipation, diarrhea, or gas and bloating, and we have documentation that a specific bacterial characteristic or function is the mechanism responsible for that benefit (as we know lowering cholesterol reduces heart disease), we cannot know which specific genetic content or characteristic would be responsible for the specific clinical outcome. The degree of sophistication of the basic science research doesn t alter these requirements. There are numerous examples for probiotics and other products in which biologically plausible mechanisms such as those cited do not translate into the expected clinical outcomes when tested in human (clinical) trials. A number of such examples for probiotics are provided in articles cited in these proceedings and in Dr. Merenstein s publications. Dr. Blumberg, in his deposition, also indicates that results from in vitro and animal studies may establish plausibility but don t consistently predict outcomes in clinical studies. Drs. Blumberg and Merenstein agree that results from in vitro and animal studies cannot be used in the absence of clinical data to support claims. Dr. Benson, in his deposition, also indicates that clinical studies 5

7 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 7 of 78 PageID: 1904 documenting benefit for constipation, diarrhea, and gas and bloating are required when drawing conclusions about biological mechanism. Thus, competent and reliable scientific evidence from clinical studies designed to yield accurate and reliable results are required to substantiate the PCH claims at issue, regardless of the presence or absence of biologically plausible mechanisms from in vitro and animal studies. 4) Epidemiologic (observational) data and assessment using the Bradford- Hill criteria are not presented related to the PCH claims and do not replace RCTs when RCTs are available or feasible Statements regarding the totality of evidence including epidemiologic (observational) data and use of the Bradford-Hill criteria to examine such data are made repeatedly. Appropriately-designed epidemiologic studies of a treatment (e.g., PCH) are typically done using large databases that assess specific outcomes identified by diagnostic coding and treatments based on pharmacy records. Such studies are generally not practical for an over-the-counter product and symptoms like constipation, diarrhea, or gas and bloating. In any event, no such epidemiological studies that assess the association between PCH (or its component species) and constipation, diarrhea, or gas and bloating with Bradford-Hill criteria have been presented. Furthermore, as reports cited by Bayer s experts (and Sir Bradford Hill s original essay) indicate, assessment of epidemiologic data using the Bradford-Hill criteria does not take the place of well-designed RCTs, but rather would be employed if RCTs were not available (if clinical or public health decisions needed to be made) or 6

8 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 8 of 78 PageID: 1905 feasible. As discussed above, this is not the case related to the PCH claims at issue. 5) Strain-specific studies are required to substantiate specific health claims such as the PCH claims regarding constipation, diarrhea, or gas and bloating. Literally dozens of articles produced in these proceedings, including articles provided by Bayer, support the need for strain-specific studies. The 2014 ISAPP consensus report, which is cited to rebut the need for strain specificity, indicates that the minimal level of evidence required for a probiotic... supplement with a specific health claim (such as the PCH claims at issue) is convincing evidence needed for specific strain(s) or strain combination in the specified health indication. Dr. Merenstein s own publications repeatedly indicate the importance of strain specificity and stress that results with specific strains or products cannot be extrapolated to other strains or products. Bayer s experts also say that common genetic content and metabolic characteristics allow extrapolation from strain to strain. However, as indicated in Section #3 of this Summary, such extrapolation for the specific symptoms of constipation, diarrhea, or gas and bloating in the PCH claims at issue is not valid. 6) The totality of evidence from studies provided in these proceedings do not provide competent and reliable scientific evidence to support the claims at issue for the PCH product (or even the PCH species). Objective review of the RCTs of PCH, or even of the bacterial species in the PCH product, that do not meet all of my study criteria (e.g., different populations, different strains) fail to substantiate claims that PCH prevents, cures, or treats 7

9 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 9 of 78 PageID: 1906 constipation, diarrhea, or gas and bloating or helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. Bayer s experts indicate there are volumes of supporting RCTs and stress the importance of examining the totality of evidence. However, they fail to mention most of the trials presented by Bayer to the FTC or other trials that have been produced during these proceedings. And, as discussed in the point-by-point responses, even the select number of studies they cite fail to provide competent and reliable scientific evidence of a benefit of PCH (or even the PCH species) for constipation, diarrhea, and gas and bloating. The following 2 paragraphs provide a brief review of 14 double-blind, placebocontrolled randomized trials of PCH or component species produced in these proceedings but not cited in the Bayer expert declarations. Review of these studies indicates a lack of competent and reliable scientific evidence substantiating the claims at issue for PCH (or even the PCH species). Most importantly, 8

10 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 10 of 78 PageID: 1907 Several trials included 2 bacterial species (but not the strains) that are in the PCH product. The largest, a high-quality trial in nearly 3000 patients, showed no suggestion of benefit, leading experts to state that this study once again underscores the value of a well-conducted, multicenter, randomized, controlled trial (RCT) in answering relevant clinical questions. More important, we are again reminded of the dangers of over-interpretation of pooling the results of small, heterogeneous trials. 2 Four other small trials, all with 75 or less patients, also assessed 2 of the PCH bacterial species, and three failed to show a significant benefit for constipation, diarrhea, or gas and bloating. Among 7 trials that included one of the PCH bacterial species only one study showed significant improvement as compared to placebo in a primary endpoint of constipation, diarrhea, or gas and bloating. Conclusion The question in this case seems to be simple: is there competent and reliable scientific evidence to substantiate the claims for PCH regarding constipation, diarrhea, or gas and bloating? The experts agree that we need to assess available research studies to address this question. Furthermore, competent and reliable scientific evidence means that the studies assessed are designed so that they yield accurate and reliable results. High-quality double-blind, placebo-controlled randomized clinical studies are well accepted as the appropriate method to yield accurate and reliable results for efficacy of a product, even for supplements. This is supported by prior publications and reports from three of Bayer s experts and by the experts in evidence- 9

11 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 11 of 78 PageID: 1908 based medicine cited in these proceedings. The multiple other issues raised by Bayer s experts do not alter the fact that, to substantiate the PCH claims at hand, clinical studies which are designed to yield accurate and reliable results and which document that PCH benefits constipation, diarrhea, or gas and bloating must be presented. Multiple potential biologic mechanisms of probiotics are presented by Bayer s experts. Attempts are made to weave a number of different articles and concepts together to suggest that specific probiotic mechanisms are documented to provide specific benefit for constipation, diarrhea, or gas and bloating. However, review of the articles and concepts reveals they merely establish biologic plausibility and do not document that a specific probiotic mechanism has a benefit for one of the specific GI symptoms. Bayer s experts agree that the precise biological mechanisms for specific GI symptoms are not known, that biologically plausible mechanisms may not translate into the expected clinical benefit when tested in human trials, and that one cannot substantiate a claim based only on preclinical (e.g., in vitro, animal) studies. Bayer s microbiology expert makes it clear that appropriate clinical trials are required to substantiate claims regarding constipation, diarrhea, or gas and bloating, even if biologically plausible mechanisms exist. The use of epidemiologic studies and Bradford-Hill criteria to assess these studies is raised by Bayer s experts. However, no such epidemiologic studies and assessment for PCH (or PCH species) and symptoms of constipation, diarrhea, or gas and bloating are presented. Furthermore, they would not replace RCTs, which are 10

12 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 12 of 78 PageID: 1909 clearly feasible for the PCH claims. Bayer s experts agree that I did an excellent job in describing how to do a good study, but reject my study design because they suggest it is not necessary for a structure-function claim or for a supplement and because physicians in practice can make clinical decisions in the absence of high-quality studies designed to yield accurate and reliable results (per the standard of care). However, these comments don t address the question at issue: is there competent and reliable scientific evidence to substantiate the PCH claims regarding constipation, diarrhea, or gas and bloating. Comments by Bayer s experts regarding study design and assessment of supporting evidence repeatedly use vague, general outcome terms such as general digestive health, healthy digestive tract, overall GI health, and wide range of therapeutic benefits. However, the focus of the PCH claims at issue relates to specific clinical outcomes of constipation, diarrhea, and gas and bloating. The greatest concerns raised by Bayer s experts with my study design seem to relate to product specificity and study population. They suggest that testing the product for which the claim is made is not necessary and state that strain-specificity is not necessary, despite dozens of articles supporting strain-specificity. Even the oftcited 2014 ISAPP consensus report indicated the need for strain specificity for claims such as the PCH claims at issue. Bayer s experts also reject the need to study the population in whom the product will be used and the claim is being made. Despite their rejection of my study design, Bayer s experts fail to elaborate 11

13 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 13 of 78 PageID: 1910 criteria for studies they believe would yield competent and reliable evidence regarding the PCH claims. Rather they state that the currently available evidence is sufficient for a structure-function claim, for a probiotic supplement, and for standard-of-care clinical practice. Even if we were to accept Bayer s experts rejection of the requirements for testing the appropriate product and study population, when higher quality studies (designed to yield accurate and reliable results) that test PCH or 1-2 PCH species in a variety of study populations are reviewed, the totality still unequivocally indicates a lack of competent and reliable scientific evidence supporting efficacy for constipation, diarrhea, or gas and bloating. POINT-BY-POINT RESPONSES Expert Declaration of Dr. Brian Fennerty 1) Dr. Fennerty s Comment: Irrefutable, high quality Level 1 evidence does not exist for these very common everyday practices in gastroenterology and general medicine, yet biological plausibility coupled with clinical experience and the totality of scientific evidence constitutes sufficient scientific evidence for clinicians in the field to recommend these treatments to patients. (p. 7) We simply do not have and it is not possible to have Level 1 evidence for every clinical decision and for every supplement. Doctors must use their judgment to consider whether other levels of evidence can show a treatment is effective. (p. 7) [A]s Dr. Laine nicely describes, these studies are the ideal form of clinical trial... But that does not mean that gastroenterologists in the field demand it even for drugs, let alone dietary supplements. If gastroenterologists did demand such evidence, we could not effectively treat most of our patients. (p. 11) 12

14 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 14 of 78 PageID: 1911 RESPONSE: As evidenced by these comments and many others, Dr. Fennerty s declaration focuses primarily on criteria for standard of care on what is needed for physicians to treat patients in practice and not on the criteria for what constitutes competent and reliable scientific evidence for a claim that a product is effective. I understand that use of probiotics is within the standard of care for physicians caring for patients in practice. However, the question I was asked to address is whether competent and reliable scientific evidence substantiates a statement or claim that PCH prevents, cures, or treats constipation, diarrhea, or gas and bloating or helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. I am not a lawyer, but as a physician I know of no standard-of-care requirement that competent and reliable scientific evidence must be available for decisions made by physicians in clinical practice. Dr. Fennerty s deposition also indicates that the question he was asked to address differs from the question I was asked to address. On p. 40 he states I was asked to give an opinion on whether there was competent and reliable evidence that would allow a physician such as myself to use this product within the claims of the PCH product. The level of evidence required to allow a physician to use a probiotic product such as PCH in clinical practice for symptoms of constipation, diarrhea, or gas and bloating per the standard of care is not the same as the competent and reliable scientific evidence required to substantiate claims that PCH prevents, cures, or treats 13

15 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 15 of 78 PageID: 1912 constipation, diarrhea, or gas and bloating or helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. 2) Dr. Fennerty s Comment: First, there is overwhelming biological plausibility that probiotics, including Lactobacillus and Bifidobacteria provide positive digestive health benefits. Key mechanisms of action include: colonic bacteria s fermentation of complex carbohydrates into short chain fatty acids, which benefit both the microbes and the host; modulation of intestinal immunity functions by increasing secretory IgA, and reducing proinflammatory cytokine production; and enhancing mucosal barrier function, and reducing pathological bacteria s ability to attach to the gut wall. (p.8) RESPONSE: I agree that pre-clinical work (e.g., in vitro, animal studies) on probiotics provides biologic plausibility for GI tract effect. However, biological plausibility merely establishes that it is reasonable to study a probiotic product in clinical trials designed to yield accurate and reliable results regarding its efficacy for constipation, diarrhea, or gas and bloating. Dr. Fennerty and numerous experts provide long lists of the possible mechanisms by which probiotics and PCH may exert effects in the GI tract. However, studies do not document that PCH (or even PCH species) is efficacious for constipation, diarrhea, or gas and bloating and do not document a specific mechanism which results in a specific clinical benefit in constipation, diarrhea, or gas and bloating (e.g., in contrast to evidence that interventions which lower cholesterol decrease heart disease). Thus, the fact that species of Bifidobacteria or of Lactobacillus may have similarities in a number of mechanisms in no way indicates that PCH strains are beneficial for constipation, 14

16 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 16 of 78 PageID: 1913 diarrhea, or gas and bloating. In his deposition, Dr. Fennerty repeatedly admits that these are merely potential mechanisms that establish biologic plausibility but not direct linked to symptoms of constipation, diarrhea, or gas and bloating: e.g., the exact mechanism of the many mechanisms by which probiotics affect the human gut and how that correlates directly to a specific symptom is unknown (p. 147). 3) Dr. Fennerty s Comment: Although these RCTs are not all Level 1 evidence and would not meet the standard for drug approval, they are sufficient for a supplement. In his report, Dr. Laine considers many of these studies irrelevant because they focused on patients with some digestive disease or condition (like IBS). But it is scientifically valid for physicians, including gastroenterologists, to extrapolate from these studies on patients with more frequent digestive symptoms to those with less severe symptoms. (p. 8-9) RESPONSE: Dr. Fennerty states that it is scientifically valid to extrapolate from studies in patients with digestive conditions such as irritable bowel syndrome (IBS). He also states that although 8 randomized controlled trials he cites are not all Level 1 evidence and would not meet the standard for drug approval, they are sufficient for a supplement. He is suggesting in his declaration that the phrase competent and reliable scientific evidence has a different meaning depending on the intervention being studied. Not only does this seem illogical scientifically, but Dr. Fennerty s own published work and publications from experts in evidence-based medicine he and Dr. Blumberg discuss (see response to Dr. Blumberg s Comment #13) do not agree with this view. 15

17 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 17 of 78 PageID: 1914 Dr. Fennerty authored an article in the scientific literature titled Traditional Therapies for Irritable Bowel Syndrome: An Evidence-Based Appraisal. 1 He states that criteria for Appropriate Design of Studies of Therapy include randomization and double-blinding. He further states that trials not meeting the criteria for appropriate design may not be reliable. For instance, trials that are not randomized and do not use concealed allocation are likely to have an overestimated treatment effect. Thus, he indicates that studies not meeting the high-quality criteria he eschews in his declaration may not produce reliable evidence and may overestimate benefit. In his article, 1 Dr. Fennerty reviews the evidence available both for medications and for a number of non-drug products including supplements (fiber supplements, Chinese herbal supplements, peppermint oil). In his evaluation of fiber supplements for treatment of IBS, Dr. Fennerty found 14 RCTs but stated the deficiencies in study methodology are such that treatment effect may be overestimated, and the reliability of the data from these studies is unknown and none of the 14 publications describes a Level I trial of fiber or bulking agents as a therapy for IBS.... accordingly, use of fiber and/or bulking agents for management of IBS cannot be reliably recommended. In his evaluation of Chinese herbal supplements, he identified one welldesigned RCT and stated that the results from this Level 1 study are likely reliable. However, he concluded that because no other confirmatory studies had been 16

18 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 18 of 78 PageID: 1915 published the data do not allow one to make any recommendation regarding this supplemental therapy for IBS. In his evaluation of peppermint oil, another over-the-counter product, he identified 6 RCTs. He noted that no trial met Level 1 criteria and that [t]he two highest-quality trials demonstrated negative results, but overall improvement was noted in some of the other studies. He concluded that use of peppermint oil extract agents for management of IBS cannot be reliably recommended. Thus, Dr. Fennerty s publication indicates that the criteria required for producing reliable evidence of benefit in studies of IBS (from which he stated it was scientifically valid to extrapolate to the PCH claims at issue) is the same for drugs and for non-drug over-the-counter products and supplements. He also agrees that consistent high-quality, Level 1 evidence is necessary to provide reliable evidence and reliably recommend non-drug products and supplements. His publication states Grade A recommendations are the only reliable grade for recommending a therapy. 1 In his declaration, Dr. Fennerty admits that applying such criteria to the evidence for the PCH claims leads to the conclusion that available evidence does not substantiate the PCH claims at issue. In his deposition testimony regarding his publication 1 on evidence-based appraisal of treatment studies, Dr. Fennerty indicates reliability has to do with the preciseness of the information, the accuracy (p. 87). Dr. Fennerty states that a study which has high-quality design criteria such as I suggest (and he suggests in his 17

19 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 19 of 78 PageID: 1916 publication 1 ) provides the most precise information (i.e., most accurate, reliable information) and it is more likely that this trial is more precise and close to the truth (p. 92, 97). Dr. Fennerty also says a trial that does not have all of those elements, its efficacy cannot be assumed to be as precise (i.e., accurate, reliable) (p. 96). He goes on to say It does not mean that the data is not reliable, and it doesn't mean that the data is not competent. It means simply that it is not as precise (p. 96). Thus, Dr. Fennerty says he will accept studies that cannot be assumed to yield as accurate and reliable results (and thus provide competent and reliable scientific evidence) because it is possible that results of the more poorly designed studies may turn out to be reliable. Although this level of evidence may be sufficient to allow physicians in practice to use a probiotic product, I do not believe it meets the criteria for competent and reliable scientific evidence as presented to me in this case. And this level of evidence clearly does not meet Dr. Fennerty s published criteria 1 to reliably recommend a supplement for treatment to physicians. 4) Dr. Fennerty s Comment: [T]here are volumes of randomized controlled clinical trials to support the use of probiotics as a supplement, including many trials on the genera and species of bacteria in PCH. (p. 8) In the case of probiotics generally and PCH specifically, the scientific literature taken as a whole clearly establishes a wide range of therapeutic benefits to patients and consumers. (p. 12) RESPONSE: Dr. Fennerty indicates that the totality of scientific evidence should be considered and indicates there are volumes of randomized controlled 18

20 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 20 of 78 PageID: 1917 trials to support the use of probiotics. He makes general comments about support the use and wide range or therapeutic benefits without focusing on the issue of preventing, curing, or treating constipation, diarrhea, or gas and bloating or helping defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. Furthermore he cites only 8 studies and ignores most of the studies (including double-blind randomized trials that he indicates are necessary to produce reliable results in his publication 1 ) produced by Bayer or referenced in these proceedings that represent the totality of evidence. The volumes of randomized controlled clinical trials cited by Dr. Fennerty in his declaration were the 8 articles summarized below: Guglielmetti et al.: This trial reported no benefit with a non-pch strain of B. bifidum in IBS patients for unvalidated secondary endpoints of frequency of bowel movements or incomplete evacuation, but did report a significant difference in favor of B. bifidum for an unvalidated secondary endpoint of bloating/distension. The authors discussed different postulated mechanisms for this clinical outcome and stated that further research is needed to investigate if the positive effects of B. bifidum MIMBb75 can be attributed to this mode of action. Guerra et al. (also FTC_PCH provided by Bayer): This trial of 1 PCH species and 2 other bacteria in children with chronic functional constipation reported no significant difference in defecation frequency and no significant difference in consistency (a p-value was 0.03 for consistency was reported at one of multiple time 19

21 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 21 of 78 PageID: 1918 points but this single p-value given multiple comparisons of a secondary endpoint is not significant). At the end of the Results section they then state that when all of the data were analyzed there was a significant difference in defecation frequency (p=0.012) but not consistency but they do not show the data leading to this statement. Regardless of outcomes, in studies of a PCH species combined with other bacteria, it is not possible to ascribe any potential benefit to the PCH species. McFarland et al. (also FTC_PCH provided by Bayer): This is a metaanalysis of 12 randomized comparisons of probiotic treatments from 7 studies for the prevention of traveler s diarrhea. There was overall benefit in the study but this was due to the probiotic yeast Saccharomyces boulardii (a non-bacterial probiotic). Among the 4 comparisons involving S. boulardii, 3 showed significant benefit and the fourth showed a non-significant treatment effect risk ratio in the direction favoring S. boulardii (risk ratio = 0.87, ). Among the 4 comparisons involving PCH species, 1 study (combination of L. acidophilus, L. bulgaricus, S. thermophilus, B. bifidum) showed benefit while 3 others with L. acidophilus showed no benefit, with treatment effect risk ratios >1 (in the direction favoring placebo). The authors stated that [s]ignificant difference in effectiveness have been reported for different species and strains of similar species of bacteria and yeasts. Unfortunately, many trials only report the genus and species and do not provide strain designations (75%) of the S. boulardii treatment arms were significantly protective of TD, but only one (13%) of the Lactobacilli trials was protective. Importantly, pooled results of PCH species studies 20

22 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 22 of 78 PageID: 1919 in this meta-analysis failed to document a benefit of probiotic vs. control with equivalent 58% cure rates in each group (risk ratio = 1). Pitkala et al. (FTC_PCH provided by Bayer): This study did not randomize patients although it stated it was an RCT. Rather, subjects in 12 wards of two nursing homes were included and the authors randomized the wards into three study groups (1 control and 2 probiotic groups). The endpoints were stated in an unclear manner; the primary endpoint was proportions of participants having bowel functioning >30% of days. The difference between B. longum and control was not significant in this primary endpoint (p=0.044 with 2 comparisons performed for the primary endpoint; a p-value <0.025 could be considered significant). Furthermore, 12% of patients were excluded from their analysis and the authors indicate that many participants were discharged, left for long periods to visit relatives, or were demented and could not be reliably followed. Madden et al. (FTC_PCH provided by Bayer): This study is not relevant to the issue of PCH species benefit for constipation, diarrhea, or gas and bloating. GI symptoms weren t assessed in this study. Margreiter et al. (FTC_PCH provided by Bayer). This study was not placebo-controlled but was a non-inferiority study in which L. gasseri and B. longum were compared to another probiotic (E. faecium). Other articles provided by Bayer to the FTC demonstrate the limitations of this study. FTC_PCH showed that the E. faecium comparator used in this study was not better than placebo in treatment 21

23 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 23 of 78 PageID: 1920 of acute diarrhea (the same indication as the Margreiter study). In addition, PCH from Bayer states Noninferiority trials may sometimes be necessary when a placebo group cannot be ethically included, but it should be recognized that the results of such trials are not as credible as those from a superiority trial. As discussed below, there is no question that a placebo group is ethical in a trial of a probiotic for acute diarrhea. Thus, Bayer s own reference suggests the design was not appropriate and its results are not as credible. Hamilton-Miller et al.: This article is a narrative review and not a randomized trial. Jiang et al. (FTC_PCH provided by Bayer): This reported no significant benefit of 3 different B. longum preparations in GI symptoms of diarrhea, bloating (meteorism), flatus frequency, or flatulence (a comparison of flatulence between control and one of the 3 B. longum preparations showed a difference in flatulence of 2.7 on a scale of 0-40 with a p=0.034; this would not be significant since it was one of 18 secondary comparisons, and a 2.7 difference on a 0-40 scale is unlikely to be clinically significant). The hypothesis was that the probiotic would improve lactose digestion (as measured by breath hydrogen excretion) and GI symptoms. Interestingly, this trial documented a significant difference in effect on the lactose malabsorption between strains of B. longum, and also documented no benefit in GI symptoms despite an improvement in lactose malabsorption. Thus, findings from this article counter Bayer s experts opinions regarding strain-specificity, predictive 22

24 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 24 of 78 PageID: 1921 value of probiotic mechanisms, and efficacy of PCH species: 1) the postulated probiotic mechanism differed across different strains of the PCH bacterial species; 2) the underlying mechanism proposed to benefit GI symptoms was not substantiated; and 3) the PCH species was not effective for constipation, diarrhea, and gas and bloating. The volumes of RCTs cited by Dr. Fennerty include articles that were not RCTs, that did not measure GI symptoms, and that failed to document benefit of PCH species. Objective review of these articles certainly does not substantiate the PCH claims at issue. In addition to discussing Dr. Fennerty s citations, we need to review the totality of evidence that has been presented in these proceedings regarding the PCH product and it component species. The following paragraphs summarize the other individual double-blind placebo-controlled randomized trials of PCH or component species in numerous populations (e.g., healthy, IBS/functional GI disorders, diarrhea, constipation, patients taking antibiotics, ulcerative colitis, preterm infants) that have been presented during these proceedings but not mentioned by Dr. Fennerty. Most were provided by Bayer with a few identified by the government. Most relevant are (very close to my requirement of not having constipation 23

25 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 25 of 78 PageID: 1922 or diarrhea at baseline). Several trials included 2 bacterial species included in the PCH product (L. acidophilus or gasseri, B. bifidum, B. longum). The largest, a high-quality trial in nearly 3000 patients showed no suggestion of benefit, 3 leading experts to state that this study once again underscores the value of a well conducted, multicenter, randomized, controlled trial (RCT) in answering relevant clinical questions. More important, we are again reminded of the dangers of over-interpretation of pooling the results of small, heterogeneous trials. 2 Five other small trials produced in these proceedings, all with 75 or less patients, also assessed 2 of the PCH bacterial species, and four failed to show a significant benefit for constipation, diarrhea, or bloating (FTC_PCH , FTC_PCH , FTC_PCH , Diop 2008). The fifth study, in 67 children aged 2 months to 7 years who were hospitalized with diarrhea, did report a decrease in the duration of diarrhea with the probiotic (FTC_PCH ). Among 7 trials that included one of the PCH bacterial species (sometimes with other non-pch bacterial species), only one study showed significant improvement as compared to placebo in a primary endpoint of constipation, diarrhea, or gas and bloating: the combination of L. acidophilus CL1285 and L. casei LBC80R reduced antibiotic-associated diarrhea 24

26 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 26 of 78 PageID: 1923 (FTC_PCH ). A study in 12 healthy subjects showed no difference in stool number or weight (diarrhea, constipation, gas/bloating not assessed) (FTC_PCH ); a study in 10 patients taking an antibiotic did not compare the difference between the two study groups and did not assess diarrhea or constipation, and reported a significant increase in stool weight and number with placebo but not probiotic (FTC_PCH ); a study of L. acidophilus NCFM and a non-pch species (B. lactis Bi-07) in 60 patients with functional GI disorders showed no benefit in primary endpoints of global relief or satisfaction with treatment or secondary endpoints of IBS severity, IBS quality of life, stool frequency, or stool consistency while at some time points benefit in bloating was seen (FTC_PCH ); a study of L. gasseri CECT5714 and a non-pch species (L. coryniformis CECT5711) in 30 healthy volunteers reported no significant difference in bowel function, bowel habits, or frequency of stool (patient-reported stool volume increased with probiotic) (FTC_PCH ); a study of B. longum plus a prebiotic with data from 14 patients with ulcerative colitis did not present data on constipation, diarrhea, or gas and bloating, and significant differences were not reported for probiotic vs. placebo in improvements in ulcerative colitis outcomes (FTC_PCH ); a study of B. longum BB536 plus L. rhamnosus GG in very-low-birth-weight preterm infants did not present data on constipation, diarrhea, or gas and bloating, and no significant difference in development of necrotizing enterocolitis was identified (FTC_PCH ). An objective review of the totality of studies cited by Dr. Fennerty and the 25

27 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 27 of 78 PageID: 1924 multiple double-blind placebo-controlled randomized trials presented during the course of these proceedings can only lead to a conclusion that competent and reliable evidence has not been provided to substantiate claims that PCH (or even the PCH species) prevents, cures, or treats constipation, diarrhea, or gas and bloating or helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. an extremely large high-quality RCT with 2 PCH species was negative, and most other studies including PCH species also failed to document significant benefit for constipation, diarrhea, and gas and bloating. As indicated in my response to Dr. Fennerty s Comment #2, Dr. Fennerty himself agrees that the available evidence does not satisfy his published criteria 1 for reliable evidence regarding supplements. 5) Dr. Fennerty s Comment: Dr. Laine also considers these studies irrelevant because they did not utilize the precise strains of probiotics in PCH. But when it comes to digestive health, our understanding of the gut microbiome teaches that these bacteria have shared genetic content and functioning across strains such that the ability to impact digestive health is not likely a strain-specific characteristic. This conclusion was recently affirmed by a consensus scientific panel. (p. 9) RESPONSE: Dr. Fennerty uses the phrase ability to impact digestive health when the issue at hand is the ability to prevent, cure, or treat constipation, diarrhea, or gas and bloating or to help defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. Genomic evidence and metabolic pathways on their own cannot establish that 26

28 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 28 of 78 PageID: 1925 PCH benefits constipation, diarrhea, and gas and bloating. The totality of evidence has not substantiated that these PCH species prevent, cure, or treat constipation, diarrhea, or gas and bloating or help defend against occasional constipation, occasional diarrhea, or occasional gas and bloating. Furthermore, as discussed in Summary Section #3 and my response to Dr. Fennerty s Comment #2, a specific mechanism or genetic content that prevents, cures, or treats constipation, diarrhea, or gas and bloating or helps defend against occasional constipation, occasional diarrhea, or occasional gas and bloating has not been established. Linking of metabolic pathways with clinical outcomes is not possible before clearcut evidence of benefit on those clinical outcomes is established. Dr. Fennerty cites a 2014 ISAPP consensus report (reference 11) as affirming that the ability to impact digestive health is not likely a strain-specific characteristic. He is correct that the report made such statements in reference to general phrases such as digestive health. He neglects to mention, however, the 2014 ISAPP consensus report indicates that the minimal level of evidence required for a probiotic... supplement with a specific health claim (such as the PCH claims at issue) is convincing evidence needed for specific strain(s) or strain combination in the specified health indication. Thus, strain specificity was endorsed in the 2014 ISAPP consensus report for claims such as those at issue for PCH. In addition, multiple other articles provided by Bayer (FTC_PCH , FTC_PCH , FTC_PCH , FTC_PCH , FTC_PCH , FTC_PCH ) or 27

29 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 29 of 78 PageID: 1926 presented during these proceedings (ACG 2007, ASM 2006, Boyle 2006, Ciorba 2012, Dunne 1999, Dunne 2001, FAOWHO 2001, FAOWHO 2002, Hickson 2011, IDF 2008, ISAPP 2009, Letter 2010, McFarland 2009, Ouwehand 2011, Quigley 2008, Ringel 2012, Ritchie 2012, Rowland 2010, Sanders 2008, Vanderhoof 2008, Verna 2010, WGO 2008, Whelan 2013) also support the importance of strain-specificity. The issue of strain specificity is discussed more extensively below related to Dr. Merenstein s declaration. Expert Declaration of Dr. Daniel Merenstein 1) Dr. Merenstein s Comment: There are many mechanisms by which probiotics are believed to exert their effects and yield positive clinical results. These mechanisms include: 1) production of antimicrobial substances; 2) binding to and penetrating gastrointestinal receptors; 3) competition for nutrients; 4) enhancement of mucosal barrier function; 5) altered immunoregulation, including both antiinflammatory and immunostimulatory responses; 6) fermentation of glucose, lactose, and fructose, which lowers fecal ph; 7) production of short-chain fatty acids and 8) bifidogenic properties. (p. 3-4) RESPONSE: Please also see my response to Dr. Fennerty s Comment #2. This lengthy list only refers to mechanism by which probiotics are believed to yield positive clinical effects. Thus, this is a list of potential or plausible mechanisms for yielding unspecified positive effects and not documentation of a specific mechanism that benefits a specific symptom such as constipation, diarrhea, or gas and bloating. Dr. Merenstein s own publications provide evidence against the idea that 28

30 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 30 of 78 PageID: 1927 biologically plausible mechanisms from preclinical studies reliably predict clinical benefit in properly done RCTs in human subjects. Reference 32 of his CV states Earlier conducted preclinical studies provide hypotheses on mechanisms of action and relevant information about the biological plausibility of the observed clinical effects on CIDs in human studies conducted with our intervention. However, this study failed to show a significant benefit in the 2 primary endpoints (p=0.91 for first primary endpoint; p=0.046 for second primary endpoint, which is not significant because statistical comparisons for 2 primary endpoints were performed) or any secondary endpoints. Reference 30 states that Dr. Merenstein chose to study B. lactis strain BB12 because of prior research regarding BB12 s survival of intestinal transit, BB12 s role in regulating digestive health, and a few promising studies regarding BB12 s role in the immune system. However, despite the biological plausibility of potential mechanisms, no significant differences in the primary or any secondary endpoints were seen in this large double-blind, placebo-controlled randomized trial. Reference 28 states that Dr. Merenstein chose to study the probiotic combination in kefir for prevention of antibiotic-associated diarrhea because [i]t is believed that these probiotics deliver beneficial bacteria to the gut, improving gastrointestinal health. However, his double-blind placebo-controlled randomized trial failed to show a benefit in the primary outcome of diarrhea or any of the secondary outcomes. In his deposition, when discussing the different mechanism underlying probiotic effects (p ), Dr. Merenstein agrees that these are potential 29

31 Case 2:07-cv JLL-JAD Document 81-1 Filed 02/17/15 Page 31 of 78 PageID: 1928 mechanisms from these species, that we do not know the precise mechanisms related to causing constipation, diarrhea, or gas and bloating, and that any or all of the 5 or 6 mechanism he listed could be responsible. Thus, Dr. Merenstein s publications and deposition testimony support my statement that these lists of mechanisms indicate biological plausibility only, but do not document that a specific mechanism benefits a specific symptom (e.g., constipation, diarrhea, gas and bloating). 2) Dr. Merenstein s Comment: [T]he three species of bacteria in PCH: Bifidobacterium bifidum, Bifidobactierum longum, and Lactobacillus gasseri. It is well established that these three species provide digestive benefits to their host. (p. 5) RESPONSE: Statements about the vague term digestive benefits are not the issue in this case. The issue is whether competent and reliable scientific evidence exists that PCH, composed of specific strains of the three aforementioned bacterial species, prevents, cures, or treats the specific symptoms of constipation, diarrhea, or gas and bloating or helps defend against the specific symptoms of occasional constipation, occasional diarrhea, or occasional gas and bloating. 3) Dr. Merenstein s Comment: Physicians practicing medicine rely on the totality of scientific evidence from many different types of studies, not just drug-level clinical trials described by Dr. Laine. (p. 6) RESPONSE: Dr. Merenstein, like Dr. Fennerty, focuses on the standard-of-care criteria for a physician in practice. Please see my response to Dr. Fennerty s 30