Raffaele Saladino E’ nato il 31 agosto 1964. Professore universitario presso l’Università degli studi della Tuscia, Raffaele Saladino è direttore del Dipartimento di Agrobiologia ed Agrochimica Educazione, studi, ed attività didattica 1989: Laurea 110/110 e lode in Chimica Industriale con indirizzo Organico/Biologico, Università “La Sapienza” Roma, dal titolo “Sintesi di
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Microsoft word - amoryn dec _15_.docCase #205 (2/24/09) BIONEURIX CORPORATION Amoryn Dietary Supplement Direct response advertising for the Amoryn dietary supplement, marketed by the BioNeurix Corporation came to the attention of the National Advertising Review Council’s Electronic Retailing Self-Regulation Program (“ERSP”) pursuant to ERSPs ongoing monitoring program. Following ERSP’s initial review of online advertising for Amoryn the following representative core claims were identified as the basis of inquiry: 1. • “The primary ingredient in AMORYN, hyperforin, is an effective treatment for • “Over 20,000 people in the United States and worldwide have successfully used AMORYN to help them lead happier, healthier lives.” • “AMORYN works by increasing the levels of all four of the brain's "feel good" neurotransmitters. By providing an all-natural boost to serotonin, dopamine, norepinephrine, and GABA, the ingredients in AMORYN can help you feel happy, calm, and confident.” • “Amoryn, the clinically proven natural anti-depressant…” • “Clinical research shows that hyperforin relieves depression as effectively as many prescription antidepressant medications (including Paxil and Prozac), but causes fewer side effects.” • “Clinical research shows that hyperforin relieves anxiety and depression as effectively as many prescription medications, but often with fewer side effects.” • “The main ingredient in AMORYN, hyperforin, is clinically proven to relieve both mild and severe depression and anxiety.” • “After six weeks, 87% of users with panic attacks report that AMORYN helps prevent and relieve their attacks. Positive results reported by 90% of users with depression and 88% with general anxiety.” • “The overwhelming majority of users rate AMORYN as more effective than either prescription antidepressant drugs or St. John's Wort supplements. Of people who have taken both AMORYN and St. John's Wort products, 76% rate AMORYN as superior while only 5% prefer other brands. And compared to antidepressant medications, 54% report that AMORYN is more effective versus only 19% who say prescription drugs are better.” • “My psychiatrist has tried a variety of drugs. but to no avail. I ordered AMORYN and, within a week, I truly started feeling better. A month ago, most of my days were spent mentally composing suicide letters, and now, those thoughts are gone and I'm able to enjoy those six beautiful grandchildren. Thank you for this miracle medicine." [Fran H, Michigan] • “It gives us the advantages of taking prescription medications to treat depression, and in my case ADHD, without the unpleasant side effects such as drowsiness.” [Frank M, Oklahoma] MARKETER’S POSITION
BioNeurix explained that Amoryn contains a St. John’s Wort extract that is standardized to contain at least 3% hyperforin, the primary active ingredient, as well as .3% hypericin. Each Amoryn tablet is 600mg and consumers are directed to take 2 capsules per day (increased to 3 tablets per day if no improvement is seen after 3-4 weeks). The marketer maintained that the presence and amount of hyperforin in Amoryn is significant because: a) the vast majority of clinical trials demonstrating the effectiveness of St. John’s Wort for mood related problems have used extracts containing at least 3% hyperforin; b) research comparing two otherwise identical St. John’s Wort extracts that differed only in the concentration of hyperforin (5% vs. 0.5%) found that the 5% extract (900 mg/day) was effective but the 0.5% extract (900 mg/day was not, demonstrating that hyperforin is the primary and necessary constituent in St. John’s Wort for mood related application; and c) unlike pharmaceutical-grade St. John’s Wort extracts used in research (and found in Amoryn), most commercial St. John’s Wort preparations available in the Unites States are not standardized for hyperforin and contain less than 1% of the ingredient. The marketer stated that there have been numerous controlled clinical trials demonstrating the efficacy of St. John’s Wort for the treatment of depression and anxiety, three of which were submitted to ERSP for its review: 1) Thirty-five subjects participated in a 12-week, randomized double blind study (“A Double-blind, Randomized Trial of St. John’s Wort, Fluoxetine and Placebo in Major Depressive Disorder” - Fava, et al) which compared a St. John’s Wort extract (900mg/day 4%-5% hyperforin) with fluoxetine/Prozac for the alleviation of a major depressive disorder. The test investigators concluded that the St. John’s Wort extract was “significantly more effective than fluoxetine.” 2) Another study entitled “Different Therapy of mild to moderate Depressive Episodes” (Freide et al) used a randomized double-blind methodology and examined two hundred forty people for mild-moderate depression over a six week period. In comparing St. John’s Wort (500mg/day) with fluoxetine (20mg/day), the test administrators noted that the St. John’s Wort extract was “[a] clinically effective alternative to fluoxetine” and “particularly effective in depressive patients suffering from anxiety problems.” 3) In “Acute treatment of moderate to severe depression with hypericum extract (St. John’s Wort): randomized controlled double blind non-inferiority trial versus paroxetine.” (Szegedi, et al), two hundred fifty one subjects were given either a St. John’s Wort extract (900mg-1880mg/day) or paroxetine/Paxil (20mg-40mg /day) and observed over a six-week period. The study authors noted that “In the treatment of moderate to severe major depression, hypericum extract WS 5570 is at least as effective as paroxetine and is better tolerated.” BioNeurix maintained that over 30 other controlled clinical trials have shown that hyperforin-rich St. John’s Wort extract to be effective when compared to other anti-depressant drugs and placebo. A 2002 overview reviewed 34 such studies (including 3,000+ patients at doses of 300-1200mg/day) and concluded, “in the medically supervised treatment of mild to moderate depression, doses of approximately 500-100 mg of extract per day of these preparations of St. John’s Wort are of comparable efficacy to synthetic antidepressants in their normally prescribed dosages.” BioNeurix added that the typical doses of Amoryn ranges from 1-3 capsules per day containing 600-1800mg/d of St. John’s Wort, the dose found effective in research. Regarding the claim that “Over 20,000 people in the United States and worldwide have successfully used AMORYN to help them lead happier, healthier lives,” the marketer informed ERSP that the figure was calculated by taking the reported success rate of Amoryn users (as reported by customers in surveys) and applying this to the total number of Amoryn users (calculated as the number of individuals customers who have purchased Amoryn). BioNeurix maintained that, in actuality, the number was calculated several years ago when only about 30,000 people had taken Amoryn and it reported that as of July 2008, over 60,000 people have taken Amoryn, thus the a more accurate estimate of successful users would be approximately 40,000-50,000 individuals. As support for the claim that “AMORYN works by increasing the levels of all four of the brain's "feel good" neurotransmitters. By providing an all-natural boost to serotonin, dopamine, norepinephrine, and GABA, the ingredients in AMORYN can help you feel happy, calm, and confident,” BioNeurix submitted three published research papers detailing the mechanism of action of Amoryn. In one study, a kinetic analysis was performed regarding the uptake of H-L-glutamate and H-GABA into synaptosomala preparations of a mouse brain. The investigators concluded that “hyperforin clearly shows a typical anit-depressant profile but seems to work at the cellular level by a completely novel mechanism related to sodium conductive pathways.” A second study tested various St. John’s Wort extract preparations and all relevant constituents as possible inhibitors of synaptosomal uptake of neurotransmitters. Hyperforin was confirmed as the major uptake inhibiting constituent of the St. John’s Wort extracts tested and an excellent correlation between the inhibition constants and the amount of hyperforin were found in the uptake systems investigated (with the exception of norepinephrine). The marketer also provided a review of current research on St. John’s Wort examining mode of action to the ingredient’s clinical efficacy. In summary, it was concluded that St. John’s Wort extract has a clear inhibitory effect on the neuronal uptake of not only serotonin noradrenalin and dopamine, but also of gamma-aminobutyric acid (GABA) and l-glutamate. In response to ERSP’s concerns about the product’s efficacy in treating anxiety disorders, the marketer contended that depression and anxiety are closely associated conditions, noting that the two disorders “are frequently comorbid (occurring together), with some finding a cormorbidity of over 50%” and that even in the absence of a comorbid anxiety disorder, anxiety and related emotions are often symptoms or features of depression and are recognized as such by clinicians for the purpose of diagnosis and treatment. BioNeurix also maintained that the neurotransmitter pathways primarily responsible for mood regulation are implicated in causing both depression and anxiety and asserted that certain Food and Drug Administration (“FDA”) approved anti-depressant drugs have now been approved by the FDA for the treatment of anxiety disorders. II. Establishment Claims As detailed in the “Performance Claims” section of the Marketer’s Position, BioNeurix submitted a number of studies to ERSP demonstrating the efficacy of Amoryn, including clinical comparisons with Prozac and Paxil. Other published studies demonstrate effectiveness when compared to other antidepressants including sertraline/Zoloft and older tricyclic antidepressants such as imipramine. The marketer noted that these studies also found a lower incidence of side effects with hyperforin-rich St. John’s Wort extract. For example, in the “Friede study” discussed previously, it was concluded that “St. John’s Wort revealed better safety and tolerability data than fluoxetine….and is better tolerated [than paroxetine].” BioNeurix stated that this conclusion is consistent with the body of research as a whole. As support for the claim that “After six weeks, 87% of users with panic attacks report that AMORYN helps prevent and relieve their attacks. Positive results reported by 90% of users with depression and 88% with general anxiety,” the marketer relied on data gathered through surveys taken by consumers. All consumers who purchased Amoryn were e-mailed approximately six-weeks after purchase with a request to take the survey. The actual survey was conducted through a website and the results are discussed on the Amoryn website along with the disclosure that these figures were collected through informal surveys, not a controlled clinical trial. Nevertheless, BioNeurix maintained that the data is accurate and a valid reflection of user experiences with Amoryn. It was also noted that when using the survey data, the marketer was carful not make objective statements about Amoryn’s effects (e.g. “Amoryn reduced the number of panic attacks for 87% of users.”). Rather, based upon the data, BioNeurix made objective claims based upon what users report (e.g. “After six weeks, 87% of users with panic attacks report that AMORYN helps prevent and relieve their attacks”). III. Consumer Testimonial Claims BioNeurix asserted that the testimonials used in its advertising are based upon the actual experiences of the individuals and provided ERSP with the documentation as support for its position. It noted that the testimonial which statement that “… I ordered AMORYN and within a week, I truly started feeling better.” is not representative of the time period in which a typical consumer experience relief. BioNeurix noted that other portions of the Amoryn.com website explicitly state that Amoryn often takes a month to begin working. It called ERSP’s attention to the “Speed of response” section on the “Doses and Directions for Use” page of the website on which consumers are provided with much more detail regarding speed of action along with a table showing response times as recorded through consumer surveys. Lastly, BioNeurix informed ERSP that to further emphasize the time in which consumers may expect to notice results, it has added disclosure language below the testimonial in question indicating that the stated results are atypical and that Amoryn must be taken for at least three weeks to begin working. As explained in the “Marketer’s Position” section of this decision, Amoryn contains a St. John’s Wort extract that is standardized to contain at least 3% hyperforin, the primary active ingredient, as well as .3% hypericin. Each Amoryn tablet is 600mg and consumers are directed to take 2 capsules per day (increased to 3 tablets per day if no improvement is seen after 3-4 weeks). The marketer has provided an abundance of testing on a St. John’s Wort extract (3% hyperforin) that is similar to the advertised Amoryn supplement with respect to treating various degrees of depression. ERSP noted that the studies submitted by BioNeurix adhered to the fundamental tenets of sound clinical research including a randomization of test subjects, a double-blind testing methodology and a control treatment. The dosage amounts administered in the testing also were consistent with the Amoryn usage instructions recommended by the manufacturer. Accordingly, ERSP determined that the marketer’s evidence provided a reasonable basis for general performance claims, as well as establishment claims that Amoryn is an effective treatment for mild to moderate depression. Conversely, ERSP did not agree that the marketer provided adequate support for the claim that “The main ingredient in AMORYN, hyperforin, is clinically proven to relieve both mild and severe depression and anxiety.” As a preliminary point, ERSP noted that the marketer has made a concerted effort in its communication of the claim in its advertising to specify that it is the main ingredient in Amoryn – hyperforin – and not the product itself, which has been subject to clinical scrutiny. ERSP has stated in previous direct response advertising reviews that an establishment claim is, in essence, a promise that the advertiser possesses scientific evidence proving or “establishing” the truth of the advertiser’s claim. Moreover, claims stating that a product or ingredient is “clinically proven” are of great significance to consumers and are, therefore, held to the highest standard of proof for efficacy (i.e., competent and reliable evidence). Some regulatory authorities will often require more than one study to support an establishment claim and, accordingly, ERSP, typically requires advertisers to provide substantiation for establishment claims in the form of reliable, well-controlled clinical testing on the advertised product. In the subject matter the marketer is primarily relying on one study to support its claim that “… hyperforin, is clinically proven to relieve … severe depression and anxiety.” As explained previously in this decision, ERSP agreed that sufficient research has been submitted to warrant the claim that the hyperforin extract at issue is effective in the acute treatment of patients with mild to moderate depression. However, ERSP does not agree that the one study being relied on by BioNeurix provides the appropriate evidence needed to support the representation that the ingredient has been “clinically proven” to relieve “severe depression.” ERSP does not dispute that the marketer’s study provides encouraging evidence regarding the effectiveness of a hypericum extract as a treatment for severe depression. However, it was difficult to definitively assess the clinical significance of the study with the omission of a placebo control. Moreover, ERSP also noted that administration of the hypericum extract in the study differed from the recommended use of product pursuant to label instructions. More specifically, according to label instructions, users are instructed to take 2 tablets of Amoryn daily (1200mg) and, if no improvement occurs, increase to three capsules daily (1800mg) after 3-4 weeks. In the study submitted by the marketer, test subjects were initially given 3 doses of the hypericum extract daily (900mg) and for patients whose total depression score had not decreased by at least 20% after two weeks of treatment (compared with baseline) treatment was increased to three doses of 600mg per (1800mg). After two weeks, approximately 56% of the subjects in the treatment group switched to the higher doses. At the end of the acute treatment phase, 86 of 122 (71%) responded to the higher treatment phase. Thus, while research concluded that 1800 mg of the hypericum extract (or 3 capsules of Amoryn) was effective for a majority of subjects with severe depression when they began taking it after two weeks, the study provides no information on the effectiveness of an initial recommended dosage (1200 mg for three weeks) of Amoryn or whether the additional week of increased dosage (the study group increased to a 1800 mg dosage after two weeks while the Amoryn label suggests doing so after three weeks if there is no improvement) had any bearing on study results. In sum, while ERSP agrees that this study produced promising results regarding the efficacy of a hypericum extract to treat severe depression, it was concluded that because there are some differences in the way consumers were instructed to take the treatment in the study as compared to the instructions on the Amoryn label, this one study alone would not be sufficient to support a claim that the ingredient has been “clinically proven” to relieve severe depression. Accordingly, ERSP agrees with the statement of the study investigators that “The convincing results for hypericum extract WB 5570 observed in this trial deserve independent confirmation by other research.” ERSP also had reservations about BioNeurix’s claim that “The main ingredient in AMORYN, hyperforin, is clinically proven to relieve anxiety.” Although ERSP agrees that BioNeurix has produced compelling research regarding the efficacy of its active ingredient to relieve depression, the evidence with respect to the ingredient’s effectiveness in treating anxiety disorders is less dispositive. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) produced by the American Psychiatric Association (APA) anxiety and depression are separate and distinct mental disorders. In addition, many scientific authorities make a similar distinction. For example, the Discovery Health website defines “anxiety” as “a vague, uncomfortable feeling of fear, dread, or danger. Anxiety disorders are a group of psychiatric conditions that involve anxiety. The problem may be real or imaginary. Symptoms can vary in severity and length. There are several types of anxiety: acute situational anxiety; generalized anxiety disorder; panic disorder; phobias and obsessive compulsive disorders.” Conversely, “depression” is identified as “an illness that involves the body, mood, and thoughts. It affects the way a person eats and sleeps, the way one feels about oneself, and the way one thinks about things. A depressive disorder is not the same as a passing blue mood. It is not a sign of personal weakness or a condition that can be willed or wished away. People with a depressive illness cannot merely "pull themselves together" and get better. Without treatment, symptoms can last for weeks, months, or years. Appropriate treatment, however, can help most people who suffer from depression.” ERSP does not dispute that depression and other mood disorders often overlap as autonomous entities with anxiety and that there may be a significant comorbidity rate between the two conditions. Nevertheless, despite the fact that there may be some like-symptoms associated with both conditions, ERSP cannot ignore the fact that anxiety and depression are characterized as distinct conditions by medical professionals and organizations and may often require different methods of treatment. In addition, supporting a claim that a product or ingredient is “clinically proven” to treat a particular condition necessitates the prerequisite evidence – i.e., reliable and competent evidence that the product effectively treats individuals afflicted with the condition. The study submitted by BioNeurix to support this claim (“Differential Therapy of mild to moderate Depressive Episodes with St. John’s wort” M. Friede et al.) investigated “the efficacy and drug safety of a special extract of Ze 117 St. John’s Wort extract vs. selective serotonin reuptake inhibitors (“SSRI”) in patients with depressive episodes under consideration of the main depressive symptoms, such as anxiety symptoms, sleep disorders, obstruction or agitation and somatic disorders.” One factor that caused ERSP reservation about the reliability of the study results was the lack of a placebo control group. As noted in the study, “the presented study may have one restriction since a placebo group was not included. Proof of efficacy would only have been practical where both treatment regimens had been investigated against placebo.” Further, the study observed certain symptoms of anxiety as they pertained to an overall depressive disorder – which was ascertained using the Hamilton depression scale. Moreover while ERSP recognizes that the St. John’s Wort extract used in the study appeared to be an effective treatment for anxiety symptoms (i.e., a 44% decrease in anxiety symptoms), anxiety was one of five symptoms of depressive disorders that were evaluated and the published article on the study provided little information about the degree of anxiety suffered by the individual patients. Similarly, ERSP could not verify that the St. John’s Wort extract administered in the study contained the same 3% standardized hyperforin and .3% hypericum as contained in Amoryn. Accordingly, ERSP determined that the results of this study alone did not provide adequate support for the claim that the hyperforin ingredient in Amoryn is an effective (or “clinically proven”) treatment for anxiety. ERSP had no reason to dispute the authenticity of the figures submitted by BioNeurix as support for the statement “Over 20,000 people in the United States and worldwide have successfully used AMORYN to help them lead happier, healthier lives,” and in the absence of any extrinsic evidence contradicting the marketer’s data, ERSP agreed that the BioNeurix’s internal data provided a reasonable basis for the claim. Similarly, ERSP determined that the marketer’s detailed research describing the activity of the primary ingredients in Amoryn provided sufficient proof for the claim “AMORYN works by increasing the levels of all four of the brain's "feel good" neurotransmitters. By providing an all-natural boost to serotonin, dopamine, norepinephrine, and GABA, the ingredients in AMORYN can help you feel happy, calm, and confident.” Lastly, with respect to the statement “The overwhelming majority of users rate AMORYN as more effective than either prescription antidepressant drugs or St. John's Wort supplements. Of people who have taken both AMORYN and St. John's Wort products, 76% rate AMORYN as superior while only 5% prefer other brands. And compared to antidepressant medications, 54% report that AMORYN is more effective versus only 19% who say prescription drugs are better,” ERSP first noted that this claim is presented on a separate page of the product website and includes material information about the nature of the survey conducted (e.g., 66 past Amoryn users); the method in which respondents were selected (e.g., e-mailed customers, all of which had purchased AMORYN between six and eight weeks prior); and other important factors regarding the survey (e.g., respondents were not compensated in any way, and the identities of the respondents were not revealed to the researchers compiling the data). BioNeurix also prominently disclosed the limitations of the survey on the website to consumers and advises them that the survey results should not be confused with results from clinical trials (“Please keep in mind that this data does not represent the results of a controlled clinical trial and should not be considered scientific proof of AMORYN's effectiveness. (For this, please review the clinical trials demonstrating the effectiveness of AMORYN's main ingredient.) This information is intended solely to give you a better idea of what current AMORYN users think about the supplement.”) Accordingly, ERSP determined that the marketer has appropriately communicated the results of its informal survey. II. Consumer Testimonial Claims According to section §255.2 of the FTC Guides on Endorsements and Testimonials: “An advertisement employing an endorsement reflecting the experience of an individual or a group of consumers on a central or key attribute of the product or service will be interpreted as representing that the endorser's experience is representative of what consumers will generally achieve with the advertised product in actual, albeit variable, conditions of use. Therefore, unless the advertiser possesses and relies upon adequate substantiation for this representation, the advertisement should either clearly and conspicuously disclose what the generally expected performance would be in the depicted circumstances or clearly and conspicuously disclose the limited applicability of the endorser's experience to what consumers may generally expect to achieve.” During the inquiry, the marketer informed ERSP that the testimonial including language stating “I ordered AMORYN and within a week, I truly started feeling better.” was not representative of the time period in which a typical consumer will experience relief and noted that other areas of the website explicitly state that Amoryn often takes a month or more to begin working. BioNeurix informed ERSP that to emphasize that this testimonial is not representative of the typical consumer experience, it would add language indicating that the experience is not typical and, in most cases, Amoryn must be taken for up to 3-4 weeks before it begins working. ERSP noted its appreciation to the marketer for its voluntary actions to clarify the extent of its consumer testimonial. Finally, ERSP determined that the consumer statement “[Amoryn] gives us the advantages of taking prescription medications to treat depression, and in my case ADHD, without the unpleasant side effects such as drowsiness” was not an inaccurate claim and supported by the materials submitted by BioNeurix. ERSP determined that the marketer’s evidence provided a reasonable basis for its general performance claims, as well as establishment claims that Amoryn is an effective treatment for “mild to moderate depression.” However, ERSP did not agree that BioNeurix provided sufficient evidence to support statements that the product’s main ingredient has been “clinically proven” to relieve “severe” depression and anxiety. ERSP also concluded that the marketer has appropriately communicated the results of its informal survey and that its internal data provided a reasonable basis for the claim that “Over 20,000 people in the United States and worldwide have successfully used AMORYN to help them lead happier, healthier lives.” Lastly, the marketer voluntarily took action to clarify the limitations of the one remaining consumer testimonial at issue in its advertising. “We agree to take this report’s findings about Amoryn’s main ingredient being “clinically proven” to relieve “severe” depression and anxiety into consideration. BioNeurix has already taken the necessary steps to change some wording on its website. These content adjustments were made after receiving advice from BioNeurix’s NARC/ERSP representative. The Amoryn website (www.amoryn.com) should now be in accordance with NARC/ERSP regulations and this report’s findings.” Copyright 2009. Council of Better Business Bureaus, Inc.
Northwest Osteoporosis Center Medical History Questionnaire Name: _________________________________ Age: _______________ Date: _______________________ Referred By: ____________________________ Gender: M F Scan No: ________________________ Wt. _________ Ht. __________ Birthdate: __________________ Ethnic Background: Caucasian African American Asian Hispanic