I urge caution with accusations
Below is a post from YMB which is interesting yet questionable, some of the accusations are strong and not sure if proofs exist. This might be good story for some investigative journalist to pursue.
Check this link to Adcom meeting from 2004 where Colman and Orloff presented and worked very closely
http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm
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Post by "knospeaba_robert"
http://messages.finance.yahoo.com/Business_%26_Finance/Investments/Stocks_%28A_to_Z%29/Stocks_A/threadview?bn=1339&tid=177714&mid=177967
If this is looked into, i am sure it would lead back to the fact that the Qnexa study writer Dr. Orloff and Dr. Colman have connections that would lead one to see foul play as possible specifically based on Colman's actions surrounding the Qnexa and Lorq panels. This was posted on the MB and I hope someone here puts some time into following up and if correct, posting it on the Deepcapture blog. To me this is the smoking gun issue at hand and serves to motivation, the only thing (other than the idea of money) that we have to show why there would be a bias.
Evidence suggests that Orloff and Colman worked closely together while at the FDA (not only on obesity related matters):
David Orloff and Eric Colman worked together on the 2004 Report of the Working Group on Obesity -
FDA Obesity Working Group Subgroup Members
THERAPEUTICS - Lead: David Orloff. Members: Eric Colman, Patricia Beaston
http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm
Eric Colman had authority to sign some documents for David Orloff. For examples:
see page 9
http://www.accessdata.fda.gov/drugsatfda...
see page 3
http://www.accessdata.fda.gov/drugsatfda...
When Orloff caused an FDA scandal he immediately found a new position at Medspace. Was this payback to Orloff for his controversial decisions and a deflection from a proper investigation?
New York Times article - December 7, 2005
A Food and Drug Administration official whose office was involved in a recent controversial application for drug approval said yesterday that he was resigning to join private industry. Dr. David Orloff, a division director who oversees the review of drugs to treat metabolic and endocrine disorders, is set to join Medpace, a contract research organization based in Cincinnati that runs clinical drug trials.
http://query.nytimes.com/gst/fullpage.ht...
Orloff was involved with qnexa at Medspace, but the level of involvement is not entirely clear:
Dr. David Orloff and his staff at Medpace, the clinical research organization that managed the qnexa clinical trials…
http://www.health2sport.com/patients-on-...
VVUS’s obesity clinical trials are being led by Dr. David Orloff, former director of the FDA’s Division of Metabolic and Endocrine Drug Products
http://obesityinvestor.typepad.com/obesi...
Dr. David Orloff, former head of the FDA’s Endocrine and Metabolism Division helped Vivus craft a data package that has a high likelihood of passing the scrutiny of the FDA.
http://www.investorvillage.com/smbd.asp?...
While at Medspace, Orloff believed that the FDA guidelines for combination drugs was irrelevant:
Dr. David Orloff served as the Director of the Division of Metabolism and Endocrinology Products at FDA from 2000-2006. Dr. Orloff felt that investors were over-interpreting FDA obesity guidelines. He believes that data to date shows qnexa to be very well tolerated and very effective, asserting that nothing so far should "sound any alarms." Dr. Orloff feels the issue of combination synergy (demonstrating 2x the weight loss of individual components) that has plagued VVUS is “ridiculous” and should “in no way be considered a requirement for approval."
http://www.investorvillage.com/mbthread....
Did he believe the FDA guidelines were irrelevant for assessing qnexa because Colman (his former close associate) was now responsible for reviewing NDAs? Orloff may have groomed Colman in how to game the approval process? The appearance of a conflict of interest gets worse...
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http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180062&tof=2&rt=1&frt=2&off=1
Copied from YMB which was posted by "erewenguy"
There has been ongoing conversation in the comments section of one of Herper's latest articles.
http://blogs.forbes.com/matthewherper/2010/10/28/vivus-diet-drug-denied/#comment-1353
The accusations were called a "conspiracy theory", so I tried to outline the situation as I see it.
...
The “conspiracy theory” arises when looking at the total picture. If this were a court of law, enough circumstantial evidence exists for a grand jury to issue an indictment. Events are presented chronologically with the best information I have:
I believe Gebbe or his associates published the first information on the topo/phen combination in 2003 (?).
The FDA obesity workshop was conducted in 2004, where Orloff was chair of the theraputics subcommittee, which included Colman. It was time to advance the concept of combination therapies. Orloff and close associate Colman are on the regulatory “cutting edge” of understanding obesity theraputics.
Orloff’s office approves qnexa trials. Orloff’s office apparently recommends monotherapy trials of lorcaserin – a modification of a discredited drug.
Orloff becomes involved in controversy over approving a drug found to be dangerous (a questionable approval).
Orloff resigns from FDA and accepts a position at Medpace, where he oversees qnexa clinical trials his office approved.
Orloff publicly states that although qnexa DOES NOT meet combination therapy efficacy guidelines, there is no reason to believe it will not be approved.
Orloff writes qnexa NDA for Vivus, who submits it to FDA-CDER (Colman's office)
Colman is a guest on a television show which features Qnexa.
Qnexa panel review is conducted with proper diligence. “Abstain” IS allowed to panel members as a valid vote. Panel recommends rejection (no abstains) and Colman is on public record that he is surprised by the recommendation.
Lorcaserin panel meets, with well documented omissions or errors in regards to science and FDA guidelines for toxicity and efficacy, and conducted with biased innuendos and comments by FDA personnel Colman and Rosebraugh throughout the meeting. Critical cancer and toxicology experts are not on the panel. During voting instructions “abstain” is explicitly NOT allowed as an option. Panel members express ignorance of cancer/risk issues and vote to reject in the absence of abstain option.
Lorcaserin CRL is issued by Colman's office. ARNA to request type A meeting to clarify FDA requirements for path to approval.
Qnexa CRL issued by Colman's office. VVUS will respond in 6 weeks. No clarifications are needed concerning path to approval.
...
There are other side-bar facts to fill out the drama, such as potential document leaks and options activity, but the information presents the highlights.
I’m really not a conspiracy theory kind of guy, so I would welcome an alternative viewpoint compatible with Occam’s razor.
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http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180091&tof=2&rt=1&frt=2&off=1
Response by "diogenes_32bc"
Here's what JL said at the BMO conference (this was after the July EMDAC) in response to a question on LorPhen:
~~~~~~~~~~~~~~~~~~~~~~~~~~
RE: Lorcaserin-phentermine study:
JL: You know, in the past, when I asked the FDA that question, they were not in favor of such a study... they discouraged that study... and we've recently seen what another company with phentermine as part of their product... some of the liabilities that phentermine brings to that product in terms of heart rate and pressure effects... and that sort of thing... so we're flexible, we're open, we'll have a dialog with the FDA later on... I should mention that phentermine is not available in Europe at all, it's not available in Canada, I don't think it's available in Japan... so it's certainly not.. something that's cookie-cutter way of losing weight throughout the world... so we'll just have to see.. how that works out... and I should also mention that since we'll be doing these agreements with countries throughout the world, we'll look at the local regs and that sort of thing.
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This is not verbatim, and is most likely not the final word on this so keep it in context.
==========================gopher_post============================
All fair questions raised by "gopher_tunnel"
“The FDA obesity workshop was conducted in 2004, where Orloff was chair of the theraputics subcommittee, which included Colman.”
Who else was in on that workshop? Do any of those names appear other places of interest?
“Orloff’s office approves qnexa trials. Orloff’s office apparently recommends monotherapy trials of lorcaserin – a modification of a discredited drug.”
What was Orloff’s role in this? Further documentation needed.
“Orloff resigns from FDA and accepts a position at Medpace, where he oversees qnexa clinical trials his office approved.”
Did he actually oversee Qnexa trials? Such a charge would need to be substantiated.
“Orloff publicly states that although qnexa DOES NOT meet combination therapy efficacy guidelines, there is no reason to believe it will not be approved.”
Link?
“Orloff writes qnexa NDA for Vivus, who submits it to FDA-CDER (Colman's office)”
Did Orloff write the NDA? Proof?
“Qnexa panel review is conducted with proper diligence. “Abstain” IS allowed to panel members as a valid vote. Panel recommends rejection (no abstains) and Colman is on public record that he is surprised by the recommendation.”
Link to Colman’s comments?
“Lorcaserin panel meets, with well documented omissions or errors in regards to science and FDA guidelines for toxicity and efficacy, and conducted with biased innuendos and comments by FDA personnel Colman and Rosebraugh throughout the meeting. Critical cancer and toxicology experts are not on the panel. During voting instructions “abstain” is explicitly NOT allowed as an option. Panel members express ignorance of cancer/risk issues and vote to reject in the absence of abstain option.”
Untrue. “Abstain” WAS an option but the panelists were pressured repeatedly to vote “yes” or “no”.
The theory may be correct, but the case requires more detail.
http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180158&tof=2&rt=1&frt=2&off=1
========================gopher post============================
Saturday, October 30, 2010
Friday, October 29, 2010
Unbiassed Reporting...Not!
Obviously Thomas Gryta of DOW JONES NEWSWIRES has a bias towards VVUS.
"Vivus Sees Pathway To 2011 Approval For Rejected Diet Drug
11:29 AM ET 10/29/10
By Thomas Gryta
NEW YORK (Dow Jones)--Despite the regulatory rejection of its weight-loss drug, Vivus Inc. (VVUS) is confident that it can meet requests from the Food and Drug Administration and get approval for its drug next year.
Late Thursday, the Mountain View, Calif., company said it received a so-called complete response letter for its drug Qnexa that requests additional information but states no need for more clinical trials at this time. The company believes that it has sufficient data to meet the agency's needs and will file a formal response in about six weeks.
The FDA request is "just a step in the process towards approval," Vivus Chief Executive Leland Wilson said on a conference call Friday. He said the FDA requests were "clear and specific" and the company will not meet with the agency before filing a response.
Vivus shares rallied on the news, trading up 26% to $7.72."
VS
"Arena Shares Drop As Diet Pill May Face Long Delay
By Thomas Gryta
NEW YORK (Dow Jones)--Arena Pharmaceuticals Inc. (ARNA) are down 2.5% as the company likely faces a long and challenging road for its weight-loss pill lorcaserin after a Food and Drug Administration rejection.
The San Diego drug maker said the FDA wants more information about cancer incidence in rat studies and requested more data on lorcaserin's effectiveness. The company may need to conduct more clinical trails to answer those requests, possibly delaying any approval for years, and raising questions about the ultimate future of the drug.
"We view the task of disproving potential negatives (cancer risk) while arguing for approval on the basis of 'marginal' efficacy to be a difficult challenge," Canaccord Adams analyst Adam Cutler said.
Arena's stock, recently at $1.59, lost almost half of its value after an FDA panel recommended against approve in September. With a significant delay for lorcaserin, trading in Arena shares may be volatile because more than 30% of its shares were sold short as of late September."
AND
OCTOBER 25, 2010, 2:26 P.M. ET
Arena Diet Drug Rejection Reflects High Bar To Treat Obesity
By Thomas Gryta
NEW YORK (Dow Jones)--The rejection of Arena Pharmaceuticals Inc. (ARNA) and Eisai Co.'s (ESALY, 4523.TO) weight-loss drug, lorcaserin, confirms the high regulatory bar for such therapies, something that may not bode well for others making the same effort.
...
The rejection is the first official feedback from the FDA on the latest crop of diet drugs. A panel of outside experts recommended against approval last month. ...........
Although the lorcaserin decision shows the FDA's seriousness, it doesn't have any direct correlation to the other two drugs because they work in a completely different manner. ..
Vivus's drug is widely expected to get a similar FDA response .., but many expect less onerous requirements for approval.
Lazard Capital Markets analyst William Tanner said he doesn't expect more pre-clinical or clinical data will be required for Qnexa, but he believes there will be questions about birth-defect risks for one of the drug's components. ..
It seems that Gryta is getting directives from above to give a better light on VVUS than on ARNA.
"Vivus Sees Pathway To 2011 Approval For Rejected Diet Drug
11:29 AM ET 10/29/10
By Thomas Gryta
NEW YORK (Dow Jones)--Despite the regulatory rejection of its weight-loss drug, Vivus Inc. (VVUS) is confident that it can meet requests from the Food and Drug Administration and get approval for its drug next year.
Late Thursday, the Mountain View, Calif., company said it received a so-called complete response letter for its drug Qnexa that requests additional information but states no need for more clinical trials at this time. The company believes that it has sufficient data to meet the agency's needs and will file a formal response in about six weeks.
The FDA request is "just a step in the process towards approval," Vivus Chief Executive Leland Wilson said on a conference call Friday. He said the FDA requests were "clear and specific" and the company will not meet with the agency before filing a response.
Vivus shares rallied on the news, trading up 26% to $7.72."
VS
"Arena Shares Drop As Diet Pill May Face Long Delay
By Thomas Gryta
NEW YORK (Dow Jones)--Arena Pharmaceuticals Inc. (ARNA) are down 2.5% as the company likely faces a long and challenging road for its weight-loss pill lorcaserin after a Food and Drug Administration rejection.
The San Diego drug maker said the FDA wants more information about cancer incidence in rat studies and requested more data on lorcaserin's effectiveness. The company may need to conduct more clinical trails to answer those requests, possibly delaying any approval for years, and raising questions about the ultimate future of the drug.
"We view the task of disproving potential negatives (cancer risk) while arguing for approval on the basis of 'marginal' efficacy to be a difficult challenge," Canaccord Adams analyst Adam Cutler said.
Arena's stock, recently at $1.59, lost almost half of its value after an FDA panel recommended against approve in September. With a significant delay for lorcaserin, trading in Arena shares may be volatile because more than 30% of its shares were sold short as of late September."
AND
OCTOBER 25, 2010, 2:26 P.M. ET
Arena Diet Drug Rejection Reflects High Bar To Treat Obesity
By Thomas Gryta
NEW YORK (Dow Jones)--The rejection of Arena Pharmaceuticals Inc. (ARNA) and Eisai Co.'s (ESALY, 4523.TO) weight-loss drug, lorcaserin, confirms the high regulatory bar for such therapies, something that may not bode well for others making the same effort.
...
The rejection is the first official feedback from the FDA on the latest crop of diet drugs. A panel of outside experts recommended against approval last month. ...........
Although the lorcaserin decision shows the FDA's seriousness, it doesn't have any direct correlation to the other two drugs because they work in a completely different manner. ..
Vivus's drug is widely expected to get a similar FDA response .., but many expect less onerous requirements for approval.
Lazard Capital Markets analyst William Tanner said he doesn't expect more pre-clinical or clinical data will be required for Qnexa, but he believes there will be questions about birth-defect risks for one of the drug's components. ..
It seems that Gryta is getting directives from above to give a better light on VVUS than on ARNA.
Wednesday, October 27, 2010
How nonprofit organizations can be bought - Article by Alicia Mundy in 2003
I read this post on YMB and that brought back some memories about a passionate obese woman talking about breast cancer at the panel meeting. I am suspicious of her testimony after reading Alicia Mundy's article yet respect her opinion if independent(not bough out)
http://www.washingtonmonthly.com/features/2001/0301.mundy.html
In this article, the head of the National Women's Health Network says their organization doesn't take money from pharmaceutical companies -- but says nothing about whether they take money from hedge funds or their employees that may be investing in the biotech sector.
For any nonprofit, you can request a copy of their Form 990s to review the donations they received for the last 3 tax filings that are available. If this information is requested in person at a nonprofit's principal office, generally the organization must provide the information that day. If the information is requested in writing, the organization usually has 30 days to comply.
The 990 will itemize the org's donations, but the names and addresses of donors will be blacked out. These might at least tell us if the groups received any unusual large donations immediately before or after the AC. Unfortunately, any donations for 2010 won't be available until after they file 2010 taxes next April.
In the meantime, a donor-disclosure law would help and there just happens to be one stalled in the Senate right now.
http://philanthropy.com/blogs/government-and-politics/donor-disclosure-bill-again-stalls-in-senate/27177
Obesity Action which has more than 18K members called for approval of new treatments
http://www.obesityaction.org/home/index.php
http://www.washingtonmonthly.com/features/2001/0301.mundy.html
In this article, the head of the National Women's Health Network says their organization doesn't take money from pharmaceutical companies -- but says nothing about whether they take money from hedge funds or their employees that may be investing in the biotech sector.
For any nonprofit, you can request a copy of their Form 990s to review the donations they received for the last 3 tax filings that are available. If this information is requested in person at a nonprofit's principal office, generally the organization must provide the information that day. If the information is requested in writing, the organization usually has 30 days to comply.
The 990 will itemize the org's donations, but the names and addresses of donors will be blacked out. These might at least tell us if the groups received any unusual large donations immediately before or after the AC. Unfortunately, any donations for 2010 won't be available until after they file 2010 taxes next April.
In the meantime, a donor-disclosure law would help and there just happens to be one stalled in the Senate right now.
http://philanthropy.com/blogs/government-and-politics/donor-disclosure-bill-again-stalls-in-senate/27177
The following organizations spoke against approval. This is highly unusual.
Someone needs to dig deeper into who invited these groups and what motivated them to speak against ARNA
National Women's Health Network http://nwhn.org/
National Research Center for Women and Families http://www.center4research.org/
Washington Center for Weight Management and Research http://www.wtmgmt.com/
Council on Size and Weight Discrimination http://www.cswd.org/
Someone needs to dig deeper into who invited these groups and what motivated them to speak against ARNA
National Women's Health Network http://nwhn.org/
National Research Center for Women and Families http://www.center4research.org/
Washington Center for Weight Management and Research http://www.wtmgmt.com/
Council on Size and Weight Discrimination http://www.cswd.org/
Obesity Action which has more than 18K members called for approval of new treatments
http://www.obesityaction.org/home/index.php
CRL Requirements and their interpretation
What do the CRL requirements for Lorcaserin mean in practice?
1. Non-clinical issues
Issue 1.1 “Detailed accounting of all microscopic pathology slides prepared from FEMALE rats that contributed to the mammary tumor incidence data in each update to the FDA and the final study report”
a. Requirement: account for all slides done on those tissues – exactly what it says – an accounting issue.
b. In total, 65+65+75 = 205 FEMALE rats were given lorcaserin along with 65 untreated control FEMALE rats - see Table 6 in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin” (Mammary Tumors).
c. This task should not take more than 4 months, leading to a revised report (if needed).
Issue 1.2 “Independent pathologists/group of pathologists to re-adjudicate all mammary and lung tissues from all FEMALE rats (205)”
a. Requirement: It is unclear why lung tissue is included here and this is a specific question for the FDA. For the mammary tissue, it appears this refers to a discrepancy between the week-96 tumor incidences at all doses and this should also be confirmed with the FDA. If this is indeed the reason for the accounting check – these independent pathologists would re-read the histological slides and give a final decision on what the true incidences are, so as to settle any misinterpretation or discrepancies.
This re-adjudication procedure should not take more than 4 months. The response does not require a new study based on advice from a non-clinical safety assessment toxicologist.
b. During the Arena conference call on October 25, 2010, the reason for the discrepancy was provided: The preliminary slides were reviewed on a set frequency by one pathologist and initial findings were sent to the FDA prior to the final submission – this was not required but was a courtesy preview for the FDA to observe the interim results. However, at the end of the study, three independent pathologists’ performed a peer review of the data and submitted their results and these were included in the final NDA.
c. The perceived discrepancy between assessments made by the different pathologists was mentioned in the section: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (5th paragraph; Mammary Tumors), where Dr. Alavi (FDA nonclinical pharmacology / toxicity presenter) makes the following statement:
“In subsequent updates and in the final study report, the incidence of adenocarcinoma in the MD and HD females was lower than that reported at week 96 (Table 7a). The incidence of adenocarcinoma increased in the controls and stayed consistent in the low dose group over the same period. The incidence of fibroadenoma increased in all dose groups from week 96 to the final study report, though the numbers notably varied in the mid- and high dose groups (Table 7b). It appears that some of the decrease in the number of adenocarcinoma after week 96 was accompanied by an increase in fibroadenoma, potentially a consequence of the sponsor/CRO reclassifying the observed tumor types.”
This raises an important question. Why did Dr. Alavi not know that the slides had been reviewed by a single pathologist during the study and then by three independent pathologists at the end of the study? It is well known that inter-observer variation can occur in assessments of this nature. This should have been taken into account, rather than implying that the sponsor/CRO had acted improperly in respect of the discrepancy in the final numbers.
Issue 1.3 “Demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is REASONABLY irrelevant to human risk assessment.”
a. Requirement: With regard to the re-adjudicated results, a statistical analysis must be conducted to assess the significance of rat incidence of fibroadenomas and adenocarcinomas with respect to human risk. This is not a new study, but a re-assessment of the previous analysis. Unless the re-adjudication accounting yields different results, then a new study will not be necessary; however, this approach should be confirmed with the FDA.
b. The results are expected to be the same. If they are the same, then Arena needs to demonstrate that the adenocarcinomas seen at the very high and toxic Lorcaserin doses, and the statistically significant increases in fibroadenomas, do not portend a risk to humans.
c. The following information is relevant to this analysis:
The incidence of malignant adenocarcinoma tumors identified in the 10 mg/kg/day female group was no different to the normally-occurring incidence of these tumors identified in the untreated control group. Furthermore, in the 30 mg/kg/day female group, a dose 24-fold greater than the anticipated human therapeutic dose, the incidence of malignant mammary tumors was no greater than the normally-occurring malignant mammary tumor incidence reported in the untreated control female rats. Only at 100 mg/kg/day was there a statistically significant increase in adenocarcinoma incidence, but this lorcaserin dose is 82-fold that intended for human use. (Note that if Arena decides to fall into the FDA ‘mechanism of action (MOA) involves prolactin’ “trap”, they will fail and spend an eternity attempting to find the answer. They should not attempt to open Pandora’s box. There are numerous drugs on the market today for which the MOA for pathology is not understood).
Although the fibroadenoma incidence in the rats was found to be statistically significant at all doses, and the practice of combining benign tumors with malignant tumors is commonly done when the cell types are the same, this does not pose a human risk for the following reasons:
· Fibroadenoma and adenocarcinoma arise from cell types with different histogenesis. Adenocarcinomas are classified under the epithelial histotype, fibroadenomas under the epithelial-stromal histotype (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989).
· Benign mammary fibroadenomas can only be transformed to malignant mammary carcinosarcoma and never to mammary adenocarcinoma (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989). These are distinctly different tumors.
· The rat model of tumorigensis closely mimics human breast tumor development.
· Fibroadenomas rarely progress to adenocarcinoma in the rat.
· Fatalities from benign fibroadenomas do not translate as a risk to humans.
· Fibroadenomas rarely progress to adenocarcinoma in the human female and are relatively common (London, et al. 1992).
Issue 1.4 “Provide ADDITIONAL DATA/INFORMATION regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.”
a. Requirement: Since brain partitioning—brain to plasma (BPD) ratio—was not determined in humans, the FDA is concerned that estimates of safety margins based on extrapolation from monkey brain-to-plasma ratios are not reliable. Additional documented information and data are required to address this issue. Proven case studies may also help to demonstrate validity, although this approach should be confirmed with the FDA.
b. An assumption made by Dr. Alavi regarding the reliability of extrapolating monkey BPD ratios to human subjects is paraphrased as follows:
Brain partitioning in human subjects was not determined. Thus, estimating safety margins based on assumptions of partitioning in human subjects is not entirely reliable. Assuming that the monkey best models human partitioning, the estimated safety margin to a non-tumorigenic dose in rats may range from 11x to 17x, with tumors associated with brain exposures that are 40x to 59x higher than clinical exposure. More conservatively, safety margins based on plasma drug levels, which is known for rats and humans, yields a safety margin to the non-tumorigenic dose in rats of 5x, with brain tumors occurring at doses of lorcaserin 17-fold higher than the clinical dose” from the section in the FDA briefing document: from the section “Genotoxicity and Carcinogenicity Assessment For Lorcaserin. (Note this abstract is paraphrased, not a verbatim quote).
c. The actual measured BPD ratio for lorcaserin is not known in humans since it is a novel new drug that has not yet been studied in this way. However, we do know:
· The BPD ratio for lorcaserin for mice is 25 times higher in the brain vs. plasma (of note, there were no brain tumors in mice including the high dose group).
· The BPD ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma.
· The BPD ratio for lorcaserin for monkeys is 10 times higher in the brain vs. plasma.
d. The solution: An extensive review on this very issue (Shen, Artru and Adkison, 2004) clearly indicates that extrapolated partitioning in human subjects can be a reliable means of estimating risk safety margins. Referring to the monkey model, the authors state:
“In the second part of our analysis, we examined the issue of whether CSF penetration studies in animals are predictive of human data. We obtained animal and human CSF data on 27 drugs, including 13 antiepileptics, 1 psychotropic drug, 5 anesthetics or analgesics, 5 antibiotics, 1 antiretroviral, and 2 anticancer drugs, and across six animal species, including rats, dogs, rabbits, cats, guinea pigs and monkeys. As can be seen in Fig. 9, there is a reasonably good correlation for the majority of drugs in this survey."
In the same article the authors conclude that:
"Despite the complexity of CSF physiology and pharmacokinetics, CSF penetration studies in animals remain a practical option for the assessment of CNS drug delivery in early preclinical drug development"
e. The interpretation: Monkey brain partition studies can, therefore, be used with reasonable assurance for estimating a drug's margin of safety in the human brain. The brain-to-plasma ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma and the for monkeys it is 10 times higher in the brain vs. plasma
f. Lorcaserin application: There is 29x more lorcaserin in the rat brain, so the dose given to rats at the LD, MD, and HD will be much higher in the CSF and therefore more toxic. In practice, this means that at any given dose, the higher the brain exposure in rats, the higher will be the estimated brain exposure in humans. Tables 13 and 14 in the FDA document in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin (Brain Astrocytoma)”:
· Brain exposure in the rat at 30mg/kg (brain tumors present in the rat) = 405-591 mcgm/ml.
· Using the brain-to-plasma ration of 10x in the monkeys (multiple the brain exposure in rats by 10).
· Brain exposure in humans at the 30 mg/kg (brain tumors present in the rat) = 40x-59x multiple of the clinical dose (10mg bid (twice a day).
· Therefore, from the Table, we can see that the margin of safety is at 11x-17x multiple of the clinical dose, which would satisfy the concern brought up in the CRL.
· The 17x dose is when the tumors first appeared (the 30 mg/kg dose). Hence the tumorigenic dose for humans, when discussing brain/plasma ratios, would then be 40-59x multiple of the clinic dose - far above the 25-fold limit dose in the FDA guidelines.
· So from the data on the male rats the risk of developing statistically nonsignificant astrocytomas in the human, assuming that this can be transferred to human risk, would only arise at 40-59 x multiple of the clinical dose. The margin of safety dose would be 17x multiple and perhaps anywhere up to 39x multiple, although the precise value would have to be determined at incremental increases in the dose of lorcaserin (which is not necessary).
· However because Dr. Alavi used plasma levels, he concluded that the nontumorigenic dose (level where there are no tumors) gave a margin of safety at only a 5x multiple of the clinical dose. Our analysis suggests that he erred in doing this.
g. Astrocytoma was only statistically significant in male rats in the high dose group, but none of these tumors was found in the female rats.
h. The solution: To address the Astrocytoma issue Arena must supply all MBTD and brain-to-plasma ratio data to FDA in a simple, easy-to-read format. Given adequate resources, this administrative task should not take long.
2. Clinical issues
Issue 2.1 Provide BLOOM-DM trial results and analysis with respect to efficacy and diabetic health factors.
a. Results on the BLOOM-DM trial results. There is nothing more to say on this point.
3. Labeling requirements
Issue 3.1 Labeling requirements will include the following.
a. Schedule IV: This is not a significant issue. Schedule IV does not necessarily preclude long-term use, although FDA may add restrictions to that effect. They did leave the door open for removal of this label later after certain post approval studies are completed.
b. Arena must discuss with FDA any nonclinical studies conducted to address abuse concerns regarding the long-term use of lorcaserin.
4. Conclusions
In conclusion, no new studies need to be done except perhaps brain partitioning studies on humans. However, this may not be necessary if the information provided above is correct. If such studies were performed, they would not be long-term experiments and could be completed in a relatively short period, and they may not even need to be carried out under GLP conditions. However, I sense Arena already has all the data required to address this particular concern. Every other aspect of the CRL involves a REVIEW of existing information, nothing else. If everything is submitted in a timely manner, the estimated timeframe for the completion of these reviews should be less than 6 months.
REFERENCES CITED
London, S.J., Connolly J.L., S.J. Schnitt, and G.A. Colditz. "A Prospective Study of Benign Breast Disease and the Risk of Breast Cancer." JAMA 267 (1992): 941-4.
Russo, Jose, Barry A. Gusterson, Adrianne E. Rogers, Irma H. Russo, Seft R. Wellings, and Matthew J. Van Zwietien. "Biology of Disease: Comparative Study of Human and Rat Mammary Tumorigenesis." Laboratory Investigation, 1990: 267.
Russo, Jose, Irma H. Russo, Matthew J. van Zwieten, Adrianne E. Rogers, and Barry A. Gusterson. "Integument and Mammary Glands of Laboratory Animals." In Classification of Neoplastic and Non-neoplastic Lesions of the Rat Mammary Gland, edited by T.C. Uones, U. Mohr and R.D. Hunt, 275-304. Berlin:Springer-Verlag, 1989.
Shen, Danny D., Alan A. Artru, and Kimberly A. Adkison. "Principles and Applicability of CSF Sampling for the Assessment of CNS Drug Delivery and Pharmacodynamics." Advanced Drug Delivery Reviews, 2004: 1825-1857.
Daniel P. Lopez, M.D., F.A.C.O.G.
Diplomate American Board of Obstetrics and Gynecology
BORG Member
Tuesday, October 26, 2010
Many people are wondering how the Drug Ombudsman Mary Kremzner responded
Many people are wondering how the Drug Ombudsman Mary Kremzner responded to comments to her. The BioWorld reported:
"FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel."
I was one who received an e-mail response and I am recording it here for others to read.
On September 27, I emailed Capt. Mary Kremzner the following message:
Dear Capt Kremzner,
I thought you may be interested in seeing this online petition being promulgated regarding the lorcaserin panel review and effect on approval:
http://www.petitiononline.com/
--
On October 21, I received from MK, the following response:
Dear R(Bud) T-----,
Thank you for communicating your concerns to the U.S. Food and Drug Administration (FDA or the Agency) about the lorcaserin advisory committee meeting. As you know, on September 16, 2010, FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (Advisory Committee) to discuss the safety and efficacy of lorcaserin, a drug developed by Arena Pharmaceuticals, Inc. (Arena) to treat obesity. The Advisory Committee—made up of physicians, scientists, statisticians, and patient and consumer representatives— reviewed extensive background information prior to the meeting. The sponsor, FDA staff, and members of the public gave presentations during the Advisory Committee meeting. After thoroughly considering all the available information, the Advisory Committee voted 9-5 to recommend that FDA not approve lorcaserin for marketing.
After the Advisory Committee meeting, FDA began receiving correspondence from numerous parties questioning the views of FDA staff and comments made by FDA staff during the meeting, as well as accusations that scientists with appropriate expertise had not evaluated lorcaserin’s safety and efficacy data. FDA takes all comments and concerns about advisory committee proceedings seriously and wants to take this opportunity to address some of the concerns about our policies and procedures.
FDA achieves its mission to protect and promote the public health through rigorous evaluation of all data submitted in support of a new drug application (NDA). Often, the data submitted raise challenging or novel scientific issues relating to the drug’s safety and/or efficacy. FDA advisory committees serve an important function by providing the Agency with an independent, expert evaluation of the data during the drug review process. FDA ensures that during the meeting, the full spectrum of views of the data are presented to the committee and that all committee members have the opportunity to ask questions and present their own views on the data. FDA staff also routinely present their own reviews, conclusions, and individual perspectives of the data. This practice ensures that differing opinions are transparently presented and debated and allows the committee to make recommendations after taking into account all perspectives. This public process helps FDA obtain expert advice during the review process and increases the transparency to those with an interest in a particular matter. Although FDA highly values the opinions of the independent experts on the committee and often incorporates those opinions into its decision-making process, FDA makes the final decision about whether a drug should be approved. Advisory committee votes and recommendations are not binding on the Agency.
FDA has strict rules governing conflicts of interest for both employees and advisory committee members. With certain limited exceptions, FDA employees and their families cannot hold a financial interest in any company that is significantly regulated by FDA. FDA employees must report their financial interests on a yearly basis and their reports are reviewed by Agency ethics staff. FDA has not been made aware of any evidence to suggest that these rules were not followed by the FDA staff at the lorcaserin Advisory Committee meeting.
Similarly, advisory committee members must report to FDA any financial interests they hold related to the subject matter of the advisory committee meeting. FDA screens advisory committee members broadly for financial or other relationships that could present even the appearance that they have conflicts of interest that could affect their impartiality. For the lorcaserin meeting, as with all advisory committee meetings, all Advisory Committee members were appropriately screened for conflicts of interest.
Although FDA strives to have broad representation of appropriate medical and scientific specialties on its advisory committees, optimal representation is often difficult to achieve given the strict conflict-of-interest regulations that apply, as well as calendar conflicts, which may limit the availability of experts for the selected meeting dates. The lorcaserin Advisory Committee included representation from the fields of Endocrinology, Cardiology, Pharmacology, Health Policy, Epidemiology, Biostatistics, Internal Medicine, and Clinical Research. In hindsight, FDA regrets that no toxicologist participated in the meeting. However, a team of FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies. Moreover, the lorcaserin carcinogenicity studies were also thoroughly reviewed and discussed by the Center for Drug Evaluation and Research (CDER) Executive Carcinogenicity Assessment Committee, and the results of this scientific assessment were included in the background documents provided to the committee and discussed in Agency presentations at the Advisory Committee meeting.
Consistent with the FDA’s policy on transparency, FDA announces the dates for advisory committee meetings in advance through publication of a notice in the Federal Register, and the Agency posts all advisory committee briefing materials on its public website 48 hours prior to the meeting. Prior to the public posting of the documents, they are kept in strict confidentiality with only the advisory committee members and the sponsor having the opportunity to review them. As soon as possible after an advisory committee meeting has concluded, a transcript of the meeting is made available on FDA’s public website. In this way, the diverse views of all participants, both FDA employees and advisory committee members, are made available to the public.
After obtaining advisory committee input on an NDA, FDA completes its review of the application and communicates its findings to the sponsor. FDA considers all of the data contained in the application and conducts its own independent analysis of the data before making a decision as to whether the benefits of the drug outweigh its risks for the proposed use. FDA believes that this rigorous review process leads to the most appropriate decisions about the safety and efficacy of proposed new drugs.
FDA remains committed to ensuring that its advisory committee process is conducted according to applicable statutes and regulations and will continue to make these proceedings transparent to the American public. With regard to the specific allegations made against FDA staff, FDA will continue to review these allegations and if misconduct is identified, will take appropriate action.
Again, we appreciate you taking the time to express your concerns.
Sincerely,
Division of Drug Information LC
Center for Drug Evaluation and Research
Food and Drug Administration
-----------------------------------------
A lot of boilerplate here, but I think we got our message through and it had on effect on the CRL sent to Arena. It also reached the media that an unprecedented amount of investor watchfulness has been established in ARNA. This can largely be attributed to the Yaho0 Message Board and this Blog Site.
"FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel."
I was one who received an e-mail response and I am recording it here for others to read.
On September 27, I emailed Capt. Mary Kremzner the following message:
Dear Capt Kremzner,
I thought you may be interested in seeing this online petition being promulgated regarding the lorcaserin panel review and effect on approval:
http://www.petitiononline.com/
--
R (Bud) T
On October 21, I received from MK, the following response:
Dear R(Bud) T-----,
Thank you for communicating your concerns to the U.S. Food and Drug Administration (FDA or the Agency) about the lorcaserin advisory committee meeting. As you know, on September 16, 2010, FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (Advisory Committee) to discuss the safety and efficacy of lorcaserin, a drug developed by Arena Pharmaceuticals, Inc. (Arena) to treat obesity. The Advisory Committee—made up of physicians, scientists, statisticians, and patient and consumer representatives— reviewed extensive background information prior to the meeting. The sponsor, FDA staff, and members of the public gave presentations during the Advisory Committee meeting. After thoroughly considering all the available information, the Advisory Committee voted 9-5 to recommend that FDA not approve lorcaserin for marketing.
After the Advisory Committee meeting, FDA began receiving correspondence from numerous parties questioning the views of FDA staff and comments made by FDA staff during the meeting, as well as accusations that scientists with appropriate expertise had not evaluated lorcaserin’s safety and efficacy data. FDA takes all comments and concerns about advisory committee proceedings seriously and wants to take this opportunity to address some of the concerns about our policies and procedures.
FDA achieves its mission to protect and promote the public health through rigorous evaluation of all data submitted in support of a new drug application (NDA). Often, the data submitted raise challenging or novel scientific issues relating to the drug’s safety and/or efficacy. FDA advisory committees serve an important function by providing the Agency with an independent, expert evaluation of the data during the drug review process. FDA ensures that during the meeting, the full spectrum of views of the data are presented to the committee and that all committee members have the opportunity to ask questions and present their own views on the data. FDA staff also routinely present their own reviews, conclusions, and individual perspectives of the data. This practice ensures that differing opinions are transparently presented and debated and allows the committee to make recommendations after taking into account all perspectives. This public process helps FDA obtain expert advice during the review process and increases the transparency to those with an interest in a particular matter. Although FDA highly values the opinions of the independent experts on the committee and often incorporates those opinions into its decision-making process, FDA makes the final decision about whether a drug should be approved. Advisory committee votes and recommendations are not binding on the Agency.
FDA has strict rules governing conflicts of interest for both employees and advisory committee members. With certain limited exceptions, FDA employees and their families cannot hold a financial interest in any company that is significantly regulated by FDA. FDA employees must report their financial interests on a yearly basis and their reports are reviewed by Agency ethics staff. FDA has not been made aware of any evidence to suggest that these rules were not followed by the FDA staff at the lorcaserin Advisory Committee meeting.
Similarly, advisory committee members must report to FDA any financial interests they hold related to the subject matter of the advisory committee meeting. FDA screens advisory committee members broadly for financial or other relationships that could present even the appearance that they have conflicts of interest that could affect their impartiality. For the lorcaserin meeting, as with all advisory committee meetings, all Advisory Committee members were appropriately screened for conflicts of interest.
Although FDA strives to have broad representation of appropriate medical and scientific specialties on its advisory committees, optimal representation is often difficult to achieve given the strict conflict-of-interest regulations that apply, as well as calendar conflicts, which may limit the availability of experts for the selected meeting dates. The lorcaserin Advisory Committee included representation from the fields of Endocrinology, Cardiology, Pharmacology, Health Policy, Epidemiology, Biostatistics, Internal Medicine, and Clinical Research. In hindsight, FDA regrets that no toxicologist participated in the meeting. However, a team of FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies. Moreover, the lorcaserin carcinogenicity studies were also thoroughly reviewed and discussed by the Center for Drug Evaluation and Research (CDER) Executive Carcinogenicity Assessment Committee, and the results of this scientific assessment were included in the background documents provided to the committee and discussed in Agency presentations at the Advisory Committee meeting.
Consistent with the FDA’s policy on transparency, FDA announces the dates for advisory committee meetings in advance through publication of a notice in the Federal Register, and the Agency posts all advisory committee briefing materials on its public website 48 hours prior to the meeting. Prior to the public posting of the documents, they are kept in strict confidentiality with only the advisory committee members and the sponsor having the opportunity to review them. As soon as possible after an advisory committee meeting has concluded, a transcript of the meeting is made available on FDA’s public website. In this way, the diverse views of all participants, both FDA employees and advisory committee members, are made available to the public.
After obtaining advisory committee input on an NDA, FDA completes its review of the application and communicates its findings to the sponsor. FDA considers all of the data contained in the application and conducts its own independent analysis of the data before making a decision as to whether the benefits of the drug outweigh its risks for the proposed use. FDA believes that this rigorous review process leads to the most appropriate decisions about the safety and efficacy of proposed new drugs.
FDA remains committed to ensuring that its advisory committee process is conducted according to applicable statutes and regulations and will continue to make these proceedings transparent to the American public. With regard to the specific allegations made against FDA staff, FDA will continue to review these allegations and if misconduct is identified, will take appropriate action.
Again, we appreciate you taking the time to express your concerns.
Sincerely,
Division of Drug Information LC
Center for Drug Evaluation and Research
Food and Drug Administration
-----------------------------------------
A lot of boilerplate here, but I think we got our message through and it had on effect on the CRL sent to Arena. It also reached the media that an unprecedented amount of investor watchfulness has been established in ARNA. This can largely be attributed to the Yaho0 Message Board and this Blog Site.
Why did Carcenogenic expert change his mind to attend Adcom in last minute?
This is an article from BIOWORLD
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56203
FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel.
Some of the FDA's outside advisers admitted during the September meeting that they were perplexed by the carcinogenicity data and lacked the expertise to weigh the decision before them.
Indeed, the 15-member panel consisted mostly of diabetes experts, with a few cardiologists and statisticians thrown in, along with a patient representative and a nonvoting pharmaceutical industry consultant.
FDA spokeswoman Karen Riley told BioWorld Today in September that "We did have an expert on rodent carcinogenicity slated to attend the meeting, but he changed his mind late in the process." Nonetheless, the FDA argued that a team of "FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies."
[Verso] Read the last paragraph, they had an expert slated and he changed his mind in the last minute, why? doesn't that smell?
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56203
FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel.
Some of the FDA's outside advisers admitted during the September meeting that they were perplexed by the carcinogenicity data and lacked the expertise to weigh the decision before them.
Indeed, the 15-member panel consisted mostly of diabetes experts, with a few cardiologists and statisticians thrown in, along with a patient representative and a nonvoting pharmaceutical industry consultant.
FDA spokeswoman Karen Riley told BioWorld Today in September that "We did have an expert on rodent carcinogenicity slated to attend the meeting, but he changed his mind late in the process." Nonetheless, the FDA argued that a team of "FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies."
[Verso] Read the last paragraph, they had an expert slated and he changed his mind in the last minute, why? doesn't that smell?
Sunday, October 24, 2010
Eisai Vote of Confidence
"Lonnel Coats, President and Chief Executive Officer of Eisai Inc., stated, "Eisai is committed to collaborating with Arena to address the FDA's requests. Obesity is an epidemic in America, and our goal is to bring lorcaserin to physicians and patients who need additional weight loss options."
With Eisai's backing, ARNA will have a deep pocket to draw from !
In the meantime, in Asia this morning 10/25/2010, Eisai share price jumps after clarification of FDA CRL is understood: http://www.google.com/finance?q=TYO:4523
With Eisai's backing, ARNA will have a deep pocket to draw from !
In the meantime, in Asia this morning 10/25/2010, Eisai share price jumps after clarification of FDA CRL is understood: http://www.google.com/finance?q=TYO:4523
Bashers Handbook - Everything you need to know about them
I am adding this only because I fear the publisher can choose to shut the website down any day and we will be at loss. This is a very helpful HANDBOOK on BASHERS.
Disclaimer: This content is COPIED and PASTED from "Message Board Fools - http://messageboardfools.com/bashers.htm",
None of this content was written by me but I fully endorse it.
Link: http://messageboardfools.com/bashers.htm
Full credit goes to "Message Board Fools" and KUDOS!!
Is the "Bashing" of a stock an essential part of the online investment landscape?
1. Be anonymous
Grade 'A' Basher:
If you post lots of old news, respond to all positive posts with a negative side. Never respond to being called a Basher, never post on another board with same alias. Can spend up to 80 hours a week Bashing a stock.
Grade 'B' Basher:
Very good way with words, always claims to be your "friend" taking the positive poster into confidence, never posts on another board, spends about 60 hours a week.
Grade 'C' Basher:
Spends less time than the others but is somewhat effective and gets a C grade due to getting excited when Bashers rules say not to get excited, spends about 40 hours a week.
Grade 'D' Basher:
Needs to learn the basics about being convincing when making a negative statement. Spends a good amount of time working the stock, maybe 20 hours a week.
Grade 'F' Basher:
A complete idiot, most readers are not convinced he knows anything about stocks in general. The type that says a stock "sucks", but gives no rationale, shows up every so often but no regular schedule.
Disclaimer: This content is COPIED and PASTED from "Message Board Fools - http://messageboardfools.com/bashers.htm",
None of this content was written by me but I fully endorse it.
Link: http://messageboardfools.com/bashers.htm
Full credit goes to "Message Board Fools" and KUDOS!!
The Basher's Handbook |
Reprinted here as a service to those who doubt this actually exists, or is simply an unfounded urban legend. |
Our Constitution guarantees us free speech and we have always valued the lessons gleaned from dissent. When does dissent cross over that imaginary line and become "Bashing"? To often we find well grounded dissent capriciously labeled as "Bashing" by over zealous investors bent on protecting a stocks reputation at any cost. The "Bashing" that is addressed on this site is quite different from dissent. The Anatomy of a Basher strives to look at the calculated erosion of confidence in a given stock. Erosion by means that are, in every sense, void of truth, hinged on deception and innuendo, and motivated by greed at the expense of others. This compendium is offered to aid in identifying the telltale signs of "Bashing", and hopefully provide a counter balance to this heretofore unchecked manipulation of investors fears for personal gain.
IS IT EASIER TO SCARE PEOPLE INTO SELLING THAN IT IS TO SCARE PEOPLE INTO BUYING A STOCK? I have asked some knowledgeable investors this question and the answer is always: "YES, OF COURSE YES!"
WHO BASHERS PREY UPON
Consider the elderly that are investing for retirement, they find their way to the message boards for validation only to see false posts about "SEC Violations" and "Class action suits"... or the head of a "typical growing family", with children to put through college, who is monitoring a message board only to read posts by a "pack of 15 to 20 Bashers" (probably 5 or 6 under various alias's) posting continuous disinformation... what do you think these new investors will do? It's safer to not buy or even sell the stock, put the money back in the bank than to deal with all this whirl wind of "unsupported" negative chaff.
The Internet has lured a whole new class of investor into the market. A new investor is just that - New! This new investor, while learning the basics, is particularly vulnerable to the tactics of professional Bashers. New investors tend to lurk in the background of message boards, content to form independent opinions based on what they read with their own eyes. Very often, honest, intelligent and cautious people can easily be overcome by a well orchestrated propaganda effort.
You must always remember that their is a lot of money to be made in just the motion of a stock UP or DOWN it doesn't matter! And Bashers have money at risk just as you do. But they have the edge of fear, lies, and falsehoods to post while preying on the un-initiated. The average investor dose not have the edge of organized deception.
Recent revelations have indicated that even Market Makers (those charged with keeping the playing field level) have been involved in stock manipulation by Bashing on a stock message board. HAVE NO DOUBT THAT THIS IS A REAL THREAT!
The Internet has lured a whole new class of investor into the market. A new investor is just that - New! This new investor, while learning the basics, is particularly vulnerable to the tactics of professional Bashers. New investors tend to lurk in the background of message boards, content to form independent opinions based on what they read with their own eyes. Very often, honest, intelligent and cautious people can easily be overcome by a well orchestrated propaganda effort.
You must always remember that their is a lot of money to be made in just the motion of a stock UP or DOWN it doesn't matter! And Bashers have money at risk just as you do. But they have the edge of fear, lies, and falsehoods to post while preying on the un-initiated. The average investor dose not have the edge of organized deception.
Recent revelations have indicated that even Market Makers (those charged with keeping the playing field level) have been involved in stock manipulation by Bashing on a stock message board. HAVE NO DOUBT THAT THIS IS A REAL THREAT!
Lesson 1: Remember, BASHERS NEVER Bash A BAD STOCK. Check the boards for stocks with no potential. They never have any Bashers. Bashers only go after stocks that are moving up or have excellent potential to do so. Bashers work to bring the price down to either increase their position at the expense of others or help a Short make their bones.
Lesson 2: BASHERS ALWAYS BRING UP OLD NEWS THAT YOU HAVE HEARD MANY TIMES. New startup companies always have a few bits of bad news. The Basher will post this over and over again. Unsophisticated Bashers will try to freshen up old news with a new date or by-line in an attempt to fool you.
Lesson 3: BASHERS POST MANY TIMES A DAY. They try to wear you out. They comment on everything, every other post, and can answer every question. THEY KNOW IT ALL! There is no positive comment they won't Bash. They try to control the board. True longs may have to confront the Bashers or they will appear to the newbies as being the people with all the information. This is best accomplished by posting positive, well researched data on the company, repetitively, while trying hard not to engage the Bashers in direct repartee. REMEMBER - LONGS... RESIST USING THE BASHERS ALIAS!
Lesson 4: BASHERS WILL LIE TO YOUR FACE. Never trust a Basher. The truth on startup companies is that they make mistakes. What new company hasn't? The Basher will compare your issue to a another companies, financials - deals - management, etc., trying to lure you into making an Apples to Oranges comparison. Remember each company is unique and while it is prudent to seek out established indicators, do so with care and don't take someone else's word for it. Strive to come up with at least a "six-pack" of indicators so your vision of the state of a company is not tied to a single barometer. Not doing so is tantamount to going to a Race Track and betting on the "Pretty Brown Horsey". BASHERS WANT TO WHISPER IN YOUR EAR - PLANT A SEED OF DOUBT, AND HOPE THAT YOU ARE NOT SAVVY ENOUGH TO RESEARCH THE TRUTH ON YOUR OWN. This is how they achieve their greatest success.
Lesson 2: BASHERS ALWAYS BRING UP OLD NEWS THAT YOU HAVE HEARD MANY TIMES. New startup companies always have a few bits of bad news. The Basher will post this over and over again. Unsophisticated Bashers will try to freshen up old news with a new date or by-line in an attempt to fool you.
Lesson 3: BASHERS POST MANY TIMES A DAY. They try to wear you out. They comment on everything, every other post, and can answer every question. THEY KNOW IT ALL! There is no positive comment they won't Bash. They try to control the board. True longs may have to confront the Bashers or they will appear to the newbies as being the people with all the information. This is best accomplished by posting positive, well researched data on the company, repetitively, while trying hard not to engage the Bashers in direct repartee. REMEMBER - LONGS... RESIST USING THE BASHERS ALIAS!
Lesson 4: BASHERS WILL LIE TO YOUR FACE. Never trust a Basher. The truth on startup companies is that they make mistakes. What new company hasn't? The Basher will compare your issue to a another companies, financials - deals - management, etc., trying to lure you into making an Apples to Oranges comparison. Remember each company is unique and while it is prudent to seek out established indicators, do so with care and don't take someone else's word for it. Strive to come up with at least a "six-pack" of indicators so your vision of the state of a company is not tied to a single barometer. Not doing so is tantamount to going to a Race Track and betting on the "Pretty Brown Horsey". BASHERS WANT TO WHISPER IN YOUR EAR - PLANT A SEED OF DOUBT, AND HOPE THAT YOU ARE NOT SAVVY ENOUGH TO RESEARCH THE TRUTH ON YOUR OWN. This is how they achieve their greatest success.
DOUBT + FEAR + LAZINESS = BAIL OUT!
This is your investment... work for it, protect it and don't panic on the words of very shadowy figure that "has your best interest in their heart". Consider that one factor: Someone you have never met, is not a member of your family, is now, out of the goodness of their hearts - GIVING YOU FREE ADVICE (that you didn't ask for). It's a no brainer. They have motives $$$$$$$$$$$$.
Lesson 5: Bashers know YOU CAN'T VERIFY THEIR STATEMENTS. That's why they make the vague statements they do. They rely on you being to lazy to research their droppings other than to scan the board for others opinions. This is particularly dangerous when you consider that Bashers work in packs and often validate and back up each others nonsense with what appears to be "innocuous and unsolicited" verification by comrade Bashers. Let's face it, we are all conditioned to "believe" everything we see in writing. If others by virtue of their "posts" also confirm this belief, then we are subconsciously doomed to swallow the hook, line and sinker... Basher - 1 Honest Investor - 0
Lesson 6: The Bashers PLAY ON YOUR LACK OF KNOWLEDGE. They can lie about information and you won't know the difference (unless you have done your own DD on the company and know the truth and facts).
Lesson 5: Bashers know YOU CAN'T VERIFY THEIR STATEMENTS. That's why they make the vague statements they do. They rely on you being to lazy to research their droppings other than to scan the board for others opinions. This is particularly dangerous when you consider that Bashers work in packs and often validate and back up each others nonsense with what appears to be "innocuous and unsolicited" verification by comrade Bashers. Let's face it, we are all conditioned to "believe" everything we see in writing. If others by virtue of their "posts" also confirm this belief, then we are subconsciously doomed to swallow the hook, line and sinker... Basher - 1 Honest Investor - 0
Lesson 6: The Bashers PLAY ON YOUR LACK OF KNOWLEDGE. They can lie about information and you won't know the difference (unless you have done your own DD on the company and know the truth and facts).
Lesson 7: Bashers play on your lack of patience. You have held a stock for a while. You knew it will be a big stock someday, but the BASHER CAN GET TO YOU BECAUSE YOU ARE TIRED OF WAITING FOR YOUR GAIN. That's when the Basher is best. You are tired. You have forgotten the goal for the stock was to hold it for one year. The Basher is bothersome, so you dump it on a bad day. Some others also dump. Then you get mad for your loss and return to let everyone know how mad you are. Then you turn into a semi-Basher as well. THE BASHER HAS WON, AND GAINED A NEW ALLY - YOU!
Lesson 8: BRING THE PRICE DOWN. That is the Basher's job. The truth is not important. Lies are the norm. Post continuously on the board every day. They are trying to scare the newbies that are just investigating a stock. They are trying to wear down the faithful longs on the board and gain free reign and control.
Lesson 8: BRING THE PRICE DOWN. That is the Basher's job. The truth is not important. Lies are the norm. Post continuously on the board every day. They are trying to scare the newbies that are just investigating a stock. They are trying to wear down the faithful longs on the board and gain free reign and control.
A BASHER HANDBOOK:
Do not underestimate a Bashers influence on a stock. The Pro's are good at what they do and what they do is profit from your losses. Below is their "hand-book". Learn from it or you will be donating your hard earned money to them!
Do not underestimate a Bashers influence on a stock. The Pro's are good at what they do and what they do is profit from your losses. Below is their "hand-book". Learn from it or you will be donating your hard earned money to them!
Rules for Successful Bashing:
1. Be anonymous
2. Use 10% fact. 90% suggestion. The facts will lend credibility to your suggestions.
3. Let others help you learn about the stock. Build rapport and a
support base before initiating your Bashing routine.
support base before initiating your Bashing routine.
4. Enter w/ humor and reply to all who reply to you.
5. Use multiple ISP's, handles and aliases.
6. Use two (2) or more aliases to simulate a discussion.
7. Do not start with an all out slam of the stock. Build softly.
8. Identify your foes (Longs) and the boards "guru" Use them to
your advantage. Lead them do not follow their lead.
your advantage. Lead them do not follow their lead.
9. Only Bash until the tide/momentum turns. Let doubt carry it the
rest of the way.
rest of the way.
10. Give the appearance of being open minded.
11. Be bold in your statements. People follow strength.
12. Write headlines in caps with catchy statements.
13. Pour it on as your position gains momentum. Not your personality.
14. Don't worry about being labeled a "Basher". Newbies won't
know your history.
know your history.
15. When identified put up a brief fight, then back off. Return in an hour unless your foe is a weak in reasoning powers.
16. Your goal is to limit the momentum of the run. Not to tank the
company or create a plunge in the stock; be subtle and consistent.
company or create a plunge in the stock; be subtle and consistent.
17. Kill the dreams of profits, not the company or the stock.
18. Use questions to create critical thinking. Statements to
reinforce facts.
reinforce facts.
19. DO NOT LIE, NAME CALL or USE PROFANITY.
20. Encourage people to call the company. 99% won't. They'll take your word for claims made. If they do call you can always find something that is inaccurate in how they report their findings.
21. Discourage people from believing Press Releases.
Encourage them to call the company. They won't out of laziness.
Encourage them to call the company. They won't out of laziness.
22. If the companies history/PR's are negative constantly point to that. Compile a list of this data prior to beginning your efforts.
23. If the price rises blame it on the hype or the PR, temporary
mass reaction, the market, etc. Anything but the stock itself.
mass reaction, the market, etc. Anything but the stock itself.
24. If other posters share your concerns, play on that and share theirs too.
25. Always cite low volume, even when it's not.
26. Three or four aliases can dominate a board and wear down the longs.
27. Bait the Longs into personal debates putting their
focus/efforts on you and not the stock or facts. Divert their attention from facts.
focus/efforts on you and not the stock or facts. Divert their attention from facts.
28. Promote other stocks that would-be investors can turn to
instead of the one your Bashing.
instead of the one your Bashing.
30. Do not fall for challenges on the "values" of what you are doing, it's a game and you are playing it with your own rules.
Grade 'A' Basher:
If you post lots of old news, respond to all positive posts with a negative side. Never respond to being called a Basher, never post on another board with same alias. Can spend up to 80 hours a week Bashing a stock.
Grade 'B' Basher:
Very good way with words, always claims to be your "friend" taking the positive poster into confidence, never posts on another board, spends about 60 hours a week.
Grade 'C' Basher:
Spends less time than the others but is somewhat effective and gets a C grade due to getting excited when Bashers rules say not to get excited, spends about 40 hours a week.
Grade 'D' Basher:
Needs to learn the basics about being convincing when making a negative statement. Spends a good amount of time working the stock, maybe 20 hours a week.
Grade 'F' Basher:
A complete idiot, most readers are not convinced he knows anything about stocks in general. The type that says a stock "sucks", but gives no rationale, shows up every so often but no regular schedule.
LEARN ABOUT HOW BASHERS WORK: For instance: did you know that some Bashers are paid?
IGNORE THEM ...learn how professional Bashers are paid: When you REPLY to Bashers you give them an opportunity to earn appox. 5-7 dollars. The service agreement they enter into with their employer states their messages will be monitored for content, profanity, lies, etc. but Overseers and the like don't have the time to check all their Bashers messages. Only occasional spot checks are done. Those who manage the Basher will generally read the headlines to see if a Basher is replying to other posters by name. That tells them the Basher isn't just "posting blindly" or repeating the same message over and over since they won't pay for those.(True to form a Basher will put the bite on anyone, even their unscrupulous employer). A Basher will attempt to milk three to five replies per post at one to two dollars each. This way the Basher spreads negative influence to as many stockholders as possible. A Basher will create this discussion thread because it takes less time reading more messages than is necessary. This ultimately allows the Basher more time to post and make money. In general, NEVER ENGAGE A BASHER. Make them read all the posts and think up ways to enter the discussion. NEVER ENGAGE A BASHER; if you do so then YOU BECOME THE BASHER,S AID! If you feel compelled to challenge a Basher do so without mentioning his/her true alias in your response. This will make it hard for the Basher to use your post as a revenue stream. Read the news, do your own homework and make your own decisions. Get real time quotes and follow the stock for a couple of weeks. Due Diligence is key here. Know that there will be a time when the stock runs up which will be followed followed by the Bashers and those that missed the boat. The Bashers will trash the stock by saying such things as "it's a Pump and Dump" and "the company is lying" and deceiving. There goal is to scare off newbies and potential new investors by "shaking" you out of your shares. Take the time to confirm your DD ,trust your own judgement and believe in yourself, pick your point of return or loss and live with it. Don't listen to hype or Bashers trust your own judgement. Live by the rules you have created .
HOW TO IDENTIFY A BASHER
1. Check the "Born on Date" Bashers create identities on a regular basis. Rarely do you find a Basher with older "Created On" date. So click on the Identity icon for more details.
2. Take the time to look at the Basher's history of Posts. Go to other boards and see if their is a pattern to the theme of the posts. Bashers rarely waste time trying to blend in with "positive" posts, unless they are cultivating a new uninformed assistant.
3. When did the Basher show up. Bashers rarely show up when activity is in at a Lull. They show up when activity up/down..
4. Bashers never answer direct questions except with another question.
5. Bashers do work in teams (sometimes themselves as a team). So be suspicious of someone showing up and automatically having a Shadow to converse with who supports their argument.
6. Bashers always select "an argument" that can never be resolved by research.
Bashers love to work in packs. It provides the quintessential cover to achieve supposedly "independent" validation of an argument. It is neither independent nor validating.
Pack Structure: Basher Packs can be comprised of any number of Bashers. They can be purposely formed within an organization or they can be "ad hoc" formed during a conclave on a particular board. In fact a pack mentality can be achieved by an ambitious "party of one" with a few select aliases.
Once a pack is formed, a leader emerges. This leader is usually acknowledged by other Bashers because of 1. Knowledge of the stock. or 2. Recognition by current board Longs (high visibility). Once established the Leader will usually work the Pack members up in to a posting frenzy. Constantly changing themes and even occasionally biting the ear of another pack member (this earns instant credibility), and it doesn't offend the bitten Basher because he/she knows it is all part of the effect. Quite sophisticated.
Pack Structure: Basher Packs can be comprised of any number of Bashers. They can be purposely formed within an organization or they can be "ad hoc" formed during a conclave on a particular board. In fact a pack mentality can be achieved by an ambitious "party of one" with a few select aliases.
Once a pack is formed, a leader emerges. This leader is usually acknowledged by other Bashers because of 1. Knowledge of the stock. or 2. Recognition by current board Longs (high visibility). Once established the Leader will usually work the Pack members up in to a posting frenzy. Constantly changing themes and even occasionally biting the ear of another pack member (this earns instant credibility), and it doesn't offend the bitten Basher because he/she knows it is all part of the effect. Quite sophisticated.
Packs will disband and slink away without notice. Usually this is the call of the Pack Leader who is adept at recognizing overplay. More often than not, Pack members must move on because they have other Bashing commitments to fulfill. They will return to the site of a good hunt over and over again, until hamstringing is achieved.
What calls a pack together. The Cry of the Leader. Certain Bashers love to work together. They know each others bite, how to feign in and out, it is a well choreographed Bash when pack members have worked together before. They constantly check their "Sites Du Jour" for signs of Pack activity. Occasionally they will throw out a "Nibbler" Bash to see if the pack responds or if not they can work the site themselves. It's all about effectiveness, time and earning money.
What calls a pack together. The Cry of the Leader. Certain Bashers love to work together. They know each others bite, how to feign in and out, it is a well choreographed Bash when pack members have worked together before. They constantly check their "Sites Du Jour" for signs of Pack activity. Occasionally they will throw out a "Nibbler" Bash to see if the pack responds or if not they can work the site themselves. It's all about effectiveness, time and earning money.
< BEWARE OF THE PACK >
Friday, October 22, 2010
FAVORABLE CRL - This is FDA's way of admitting they made a mistake
Lonnel Coats, President and Chief Executive Officer of Eisai Inc., stated, "Eisai is committed to collaborating with Arena to address the FDA's requests. Obesity is an epidemic in America, and our goal is to bring lorcaserin to physicians and patients who need additional weight loss options."
ADAM F, Jim Edmund's, Derek Lowe, Ruthanne Russel Williams and other so called journalists with their ulterior motives( very transparent) will BASH this in just matter of time.
Spin this; say this is END of the world for ARNA, let the GAMES begin.
http://finance.yahoo.com/news/FDA-Issues-Complete-Response-prnews-3589036116.html?x=0&.v=1
Excerpt from Arena's news release
The FDA has completed its review of the NDA and determined that it cannot approve the application in its present form. In the CRL, the FDA outlined the non-clinical and clinical reasons for their decision.
The non-clinical issues identified by the FDA included diagnostic uncertainty in the classification of mammary masses in female rats, unresolved exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma, and unidentified mode of action and unclear safety margin for lorcaserin-emergent brain astrocytoma.
The CRL included the following requests related to the non-clinical issues: provide a detailed accounting of all slides prepared from female rats that contributed to mammary tumor incidence data in each update to the FDA and to the final study report; in consultation with the FDA, identify an independent pathologist or group of pathologists to re-adjudicate all mammary and lung tissues (neoplastic and nonneoplastic lesions) from all female rats; demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is reasonably irrelevant to human risk assessment; and provide additional data/information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.
With respect to the clinical reasons, the FDA stated in the CRL that the weight loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes is marginal and recommended that Arena submit the final study report of the BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) trial. The FDA also stated in the letter that in the event evidence cannot be provided to alleviate concern regarding clinical relevance of the tumor findings in rats, additional clinical studies may be required to obtain a more robust assessment of lorcaserin's benefit-risk profile.
--------------------------------------------------------------
Respected Dr. Daniel's comments:
Here are my initial thoughts in the middle of the night
I think it is positive on several points:
1. Nonclinical issues
- Accounting issue - easily resolved - to make up for the discrepancy between week 96 and final NDA incidence of fibroadenomas and adenocarcinomas
- "demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is reasonably irrelevant to human risk assessment" - I think that this has already been proven - the key words - apparent and reasonably irrelevant - this can be taken from my letter directly and has been done - Arena just has to provide it.
- "provide additional data/information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins" should not be a problem
2. Clinical issues
NO NEW STUDIES - will accept BLOOM -DM results. Study already completed, results within a few weeks to 2 months. If the numbers are good then we have a Slam-dunk
Finally "The FDA also stated in the letter that in the event evidence cannot be provided to alleviate concern regarding clinical relevance of the tumor findings in rats, additional clinical studies may be required to obtain a more robust assessment of lorcaserin's benefit-risk profile" Again cancer expert Dr. Gary Williams will be pivotal here. What this sounds like to me is that they have conceded that their conclusions regarding the rat studies were unjustifed and erroneous. They sound like they just want an explanation of why the findings are not relevant to human risk. I believe we have shown that conclusively and they have all the information we have discussed and was sent to them by myself and others.
They have presented a CRL that is in effect a 6 month review or less, maybe 3 months - it will depend how long it will take the pathologists to go over all the slides
And finally a labelling requirement - Schedule IV
From the DEA website:
Schedule IV
• The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III.
• The drug or other substance has a currently accepted medical use in treatment in the United States.
• Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.
• Examples of drugs included in schedule IV are Darvon®, Talwin®, Equanil®, Valium®, and Xanax®.
This is not a problem - it just requires the physician to have a DEA license with Schedule IV prescribing privileges - which almost all physicians have.
However they provided the following path to remove this label: The CRL provided the opportunity to complete preclinical studies that may lead to a different recommendation - again this refers back to the nonclinical issues.
Overall, in my opinion, a very soft and manageable CRL. It's late at night and I am just quickly jotting down a synopsis - after some rest hope to process this more - however I think the jist of it will be the same.
Daniel
UCLA MD
http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=170527&mid=170527&tof=5&frt=2
-----------------------------------------------------------
ADAM F, Jim Edmund's, Derek Lowe, Ruthanne Russel Williams and other so called journalists with their ulterior motives( very transparent) will BASH this in just matter of time.
Spin this; say this is END of the world for ARNA, let the GAMES begin.
http://finance.yahoo.com/news/FDA-Issues-Complete-Response-prnews-3589036116.html?x=0&.v=1
Excerpt from Arena's news release
The FDA has completed its review of the NDA and determined that it cannot approve the application in its present form. In the CRL, the FDA outlined the non-clinical and clinical reasons for their decision.
The non-clinical issues identified by the FDA included diagnostic uncertainty in the classification of mammary masses in female rats, unresolved exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma, and unidentified mode of action and unclear safety margin for lorcaserin-emergent brain astrocytoma.
The CRL included the following requests related to the non-clinical issues: provide a detailed accounting of all slides prepared from female rats that contributed to mammary tumor incidence data in each update to the FDA and to the final study report; in consultation with the FDA, identify an independent pathologist or group of pathologists to re-adjudicate all mammary and lung tissues (neoplastic and nonneoplastic lesions) from all female rats; demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is reasonably irrelevant to human risk assessment; and provide additional data/information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.
With respect to the clinical reasons, the FDA stated in the CRL that the weight loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes is marginal and recommended that Arena submit the final study report of the BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) trial. The FDA also stated in the letter that in the event evidence cannot be provided to alleviate concern regarding clinical relevance of the tumor findings in rats, additional clinical studies may be required to obtain a more robust assessment of lorcaserin's benefit-risk profile.
--------------------------------------------------------------
Respected Dr. Daniel's comments:
Here are my initial thoughts in the middle of the night
I think it is positive on several points:
1. Nonclinical issues
- Accounting issue - easily resolved - to make up for the discrepancy between week 96 and final NDA incidence of fibroadenomas and adenocarcinomas
- "demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is reasonably irrelevant to human risk assessment" - I think that this has already been proven - the key words - apparent and reasonably irrelevant - this can be taken from my letter directly and has been done - Arena just has to provide it.
- "provide additional data/information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins" should not be a problem
2. Clinical issues
NO NEW STUDIES - will accept BLOOM -DM results. Study already completed, results within a few weeks to 2 months. If the numbers are good then we have a Slam-dunk
Finally "The FDA also stated in the letter that in the event evidence cannot be provided to alleviate concern regarding clinical relevance of the tumor findings in rats, additional clinical studies may be required to obtain a more robust assessment of lorcaserin's benefit-risk profile" Again cancer expert Dr. Gary Williams will be pivotal here. What this sounds like to me is that they have conceded that their conclusions regarding the rat studies were unjustifed and erroneous. They sound like they just want an explanation of why the findings are not relevant to human risk. I believe we have shown that conclusively and they have all the information we have discussed and was sent to them by myself and others.
They have presented a CRL that is in effect a 6 month review or less, maybe 3 months - it will depend how long it will take the pathologists to go over all the slides
And finally a labelling requirement - Schedule IV
From the DEA website:
Schedule IV
• The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III.
• The drug or other substance has a currently accepted medical use in treatment in the United States.
• Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.
• Examples of drugs included in schedule IV are Darvon®, Talwin®, Equanil®, Valium®, and Xanax®.
This is not a problem - it just requires the physician to have a DEA license with Schedule IV prescribing privileges - which almost all physicians have.
However they provided the following path to remove this label: The CRL provided the opportunity to complete preclinical studies that may lead to a different recommendation - again this refers back to the nonclinical issues.
Overall, in my opinion, a very soft and manageable CRL. It's late at night and I am just quickly jotting down a synopsis - after some rest hope to process this more - however I think the jist of it will be the same.
Daniel
UCLA MD
http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=170527&mid=170527&tof=5&frt=2
-----------------------------------------------------------
FDA Adcom meeting transcript
Link to the Adcom meeting transcript
http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm
http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm
oom-DM Data May Save The Day With the FDA
This message got repeatedly rejected on the Yahoo board...but the title stuck!
I agree that the Bloom-DM sample size may not be enough to sway the vote on Lorcaserin as an obesity drug, but by adding significant improvement in combating Type II diabetes, the FDA may be swayed to approve.
My guess is that it will show an improved reduction in glucose levels in the blood stream. While weight reduction is important to the obesity issue, they have have specifically included people who have type II diabetes and would give the FDA a more compelling case to approve besides weight reduction.
--------------------------------
From the Clinical trials web site:
http://clinicaltrials.gov/ct2/show/NCT00603291?term=b loom&rank=6
Official Title: A 52-Week, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Safety and Efficacy of Lorcaserin Hydrochloride in Overweight and Obese Patients With Type 2 Diabetes Mellitus Managed With Oral Hypoglycemic Agent(s)
Further study details as provided by Arena Pharmaceuticals:
Primary Outcome Measures:
* Proportion (%) of patients achieving > or = 5% weight reduction at Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
* Change in body weight (kg) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in glycemic control (i.e., HbA1c, fasting glucose, and use of medications for diabetes) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in waist and hip measurements from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in total fat and lean body mass between Baseline and Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in blood pressure (systolic and diastolic) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in Quality of Life measures from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
Estimated Enrollment: 750
Study Start Date: December 2007
Estimated Study Completion Date: May 2010
Estimated Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Eligibility
Ages Eligible for Study: 18 Years to 65 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
* Overweight/obese men and women with type 2 diabetes mellitus that is managed with oral anti-hyperglycemic agent(s).
* Body mass index (BMI) 27 to 45 kg/m2, inclusive.
* Ability to complete a 1 year study
Exclusion Criteria:
* Pregnancy
* Use of insulin in any form, exenatide (Byetta) or pramlintide (Symlin) within 3 months prior to screening
* History of symptomatic heart valve disease
* Serious or unstable current or past medical conditions
I agree that the Bloom-DM sample size may not be enough to sway the vote on Lorcaserin as an obesity drug, but by adding significant improvement in combating Type II diabetes, the FDA may be swayed to approve.
My guess is that it will show an improved reduction in glucose levels in the blood stream. While weight reduction is important to the obesity issue, they have have specifically included people who have type II diabetes and would give the FDA a more compelling case to approve besides weight reduction.
--------------------------------
From the Clinical trials web site:
http://clinicaltrials.gov/ct2/show/NCT00603291?term=b loom&rank=6
Official Title: A 52-Week, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Safety and Efficacy of Lorcaserin Hydrochloride in Overweight and Obese Patients With Type 2 Diabetes Mellitus Managed With Oral Hypoglycemic Agent(s)
Further study details as provided by Arena Pharmaceuticals:
Primary Outcome Measures:
* Proportion (%) of patients achieving > or = 5% weight reduction at Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
* Change in body weight (kg) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in glycemic control (i.e., HbA1c, fasting glucose, and use of medications for diabetes) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in waist and hip measurements from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in total fat and lean body mass between Baseline and Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in blood pressure (systolic and diastolic) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
* Change in Quality of Life measures from Baseline to Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
Estimated Enrollment: 750
Study Start Date: December 2007
Estimated Study Completion Date: May 2010
Estimated Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Eligibility
Ages Eligible for Study: 18 Years to 65 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
* Overweight/obese men and women with type 2 diabetes mellitus that is managed with oral anti-hyperglycemic agent(s).
* Body mass index (BMI) 27 to 45 kg/m2, inclusive.
* Ability to complete a 1 year study
Exclusion Criteria:
* Pregnancy
* Use of insulin in any form, exenatide (Byetta) or pramlintide (Symlin) within 3 months prior to screening
* History of symptomatic heart valve disease
* Serious or unstable current or past medical conditions
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