Sept 20, 2010
Margaret Hamburg, M.D.
Commissioner, Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993
Dear Dr. Hamburg,
I write this e-mail to you in hope that FDA will do the right thing in case of Lorqess a novel compound developed by Arena Pharmaceuticals for treating obese patients.
From FDAs own guidance on carcenogenicity studies
"It has been agreed that if a drug is only positive in rodents at doses above those producing a 25 fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans. I would like you to note that Rodents were dosed 84 fold, hence by FDA' own guidelines Rat Tumor issue should never have been the focal point of discussion. It is a non issue which was highlighted to panelists who were not carcenogenic experts.
Excerpt from FDA guidelines
Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074919.pdf
"Note 11
It has been agreed that if a drug is only positive in rodents at doses above those producing a 25 fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans.
It has been shown that systemic exposure comparisons between rodents and humans are better estimated by a dose using mg/m2 than using mg/kg (see Note 3 above). Therefore, the human dose should be at least 25-fold lower on a mg/m2 basis than the high dose in the carcinogenicity study. The factor 6-7 (6.5) is used to convert rat doses from mg/kg to mg/m2 and the factor 40 is used to convert human doses from mg/kg to mg/m2. Thus, the estimated systemic exposure ratio of 25-fold rodent/human is equal to about a 25-fold mg/m2 ratio or a 150-fold mg/kg ratio (150 ≈ 25 x 40/6.5). Therefore a human dose below 10 mg/kg/day (about 500 mg/day or less) could be tested in rats at 1500 mg/kg as the high dose."
I disagree with the advisory committee vote on 9-16-2010 which was 9 to 5 against Lorcaserin(Lorqess). Lorcaserin clearly met one of two of the pre-established 2007 criteria for efficacy on obesity drugs. I would love to see obese patients have the option to take Lorcaserin and lose an average of 17 pounds in a year, to have 2/3 of obese patients on Lorcaserin lose 26 pounds in a year, and to have 1/4 of obese patients lose 35 pounds in a year.
Regarding the rat studies, cancer expert Gary Williams from new york said that the cancers seen in one species of rat did not apply to humans, that excess cancer was not seen in mice, and that excess cancer was not seen in the human studies. A clear distinction must be made between Fibroadenomas (benign) and Adenocarcinomas, (malignant) in the breast. As I understand it, the dose of Lorcaserin in the rats had to be 82 times that of the human dose to cause the Adenocarcinomas. The right thing for the FDA to do is to review all rat data in detail and if that is not applicable to humans then Approve Lorqess and let physicians and patients have an additional option to choose from.
Margaret Hamburg, M.D.
Commissioner, Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993
Dear Dr. Hamburg,
I write this e-mail to you in hope that FDA will do the right thing in case of Lorqess a novel compound developed by Arena Pharmaceuticals for treating obese patients.
From FDAs own guidance on carcenogenicity studies
"It has been agreed that if a drug is only positive in rodents at doses above those producing a 25 fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans. I would like you to note that Rodents were dosed 84 fold, hence by FDA' own guidelines Rat Tumor issue should never have been the focal point of discussion. It is a non issue which was highlighted to panelists who were not carcenogenic experts.
Excerpt from FDA guidelines
Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074919.pdf
"Note 11
It has been agreed that if a drug is only positive in rodents at doses above those producing a 25 fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans.
It has been shown that systemic exposure comparisons between rodents and humans are better estimated by a dose using mg/m2 than using mg/kg (see Note 3 above). Therefore, the human dose should be at least 25-fold lower on a mg/m2 basis than the high dose in the carcinogenicity study. The factor 6-7 (6.5) is used to convert rat doses from mg/kg to mg/m2 and the factor 40 is used to convert human doses from mg/kg to mg/m2. Thus, the estimated systemic exposure ratio of 25-fold rodent/human is equal to about a 25-fold mg/m2 ratio or a 150-fold mg/kg ratio (150 ≈ 25 x 40/6.5). Therefore a human dose below 10 mg/kg/day (about 500 mg/day or less) could be tested in rats at 1500 mg/kg as the high dose."
I disagree with the advisory committee vote on 9-16-2010 which was 9 to 5 against Lorcaserin(Lorqess). Lorcaserin clearly met one of two of the pre-established 2007 criteria for efficacy on obesity drugs. I would love to see obese patients have the option to take Lorcaserin and lose an average of 17 pounds in a year, to have 2/3 of obese patients on Lorcaserin lose 26 pounds in a year, and to have 1/4 of obese patients lose 35 pounds in a year.
Regarding the rat studies, cancer expert Gary Williams from new york said that the cancers seen in one species of rat did not apply to humans, that excess cancer was not seen in mice, and that excess cancer was not seen in the human studies. A clear distinction must be made between Fibroadenomas (benign) and Adenocarcinomas, (malignant) in the breast. As I understand it, the dose of Lorcaserin in the rats had to be 82 times that of the human dose to cause the Adenocarcinomas. The right thing for the FDA to do is to review all rat data in detail and if that is not applicable to humans then Approve Lorqess and let physicians and patients have an additional option to choose from.
My concerns and questions about how FDA handled the Lorqess drug review meeting
1. Can FDA change guidelines after approving clinical trails, if yes then would that apply to clinical trails that commenced prior to the date of new guideline issuance?
2. If FDA was concerned about rat tumors then why did they even allow Arena to start clinical trials (Phase I, II, and III) and try it on 8000+ humans? When Arena discussed the data with FDA; why did FDA not stop the clinical trials?
3. Why did FDA not have a Carcinogenic expert and Oncologist on the panel if the focal point of the meeting would be Rat Tumors? This drug did not cause tumors in Monkey's or Mice, why was that not discussed at all?
4. Why did Eric Colman make public statements after Vivus' Qnexa review like
"When you listen to even the 'no' voters, you got the sense a lot of people had a little bit of hesitancy," FDA Deputy Director for Endocrine Products Eric C. Colman, MD, said in a news conference. "They were not strongly against the drug but had lingering concerns that made them vote 'no.'"
“I was a little surprised that the vote went as it did,” said Eric Colman, the deputy director of the FDA Division of Metabolism and Endocrinology Products, in a press briefing after the meeting. He declined to elaborate.
Is this legal or is it violation of code of conduct?
5. Can FDA personnel play scare tactics by making intimidating statements like
"your name would be forever attached to a drug that you helped approve and then recalled"
So does this mean Eric Colman thought this drug would be recalled if approved? On what basis? scientific or non-scientific?
6. When FDA is the final authority to approve or deny why would panelists names be of such an importance?
7. Last but not the least, how is it that one nanosecond after FDA briefing docs are made public the analysts and MSM have articles up on line and ready to go? Did they take a speed reading class? And, more to the point: why did they have short positions as of about a month ago, before there was any real news to trade on?
Were the documents leaked ahead of time?
Meridia; a drug that is much less efficacious and actually doesn't even meet FDA' 2007 guidelines and has lot more side effects was reviewed by pretty much the same panel and surprisingly tumors were not the topic of discussion. Meridia is pulled out of Europe for its safety concerns, why is it still available in the US market? It is my understanding that any drug can be dangerous at a toxic dose so not sure why that is an issue with Lorqess. Denying a novel compound which improved life style,controlled sugar levels, controlled LDL and met FDA efficacy and safety guidelines is a mistake that should be avoided, I plead you and FDA to review this matter as it deserves utmost attention.
Note: Lorqess met both efficacy and safety benchmarks, Valvular issues were ruled out in human trails.
I'd also like you to investigate the events and I hope you take necessary action to prevent any unprofessional conduct of any FDA employee.
Full disclosure: I have a small LONG position in ARNA but that doesn't make this letter invalid by any means.
Sincerely,
1. Can FDA change guidelines after approving clinical trails, if yes then would that apply to clinical trails that commenced prior to the date of new guideline issuance?
2. If FDA was concerned about rat tumors then why did they even allow Arena to start clinical trials (Phase I, II, and III) and try it on 8000+ humans? When Arena discussed the data with FDA; why did FDA not stop the clinical trials?
3. Why did FDA not have a Carcinogenic expert and Oncologist on the panel if the focal point of the meeting would be Rat Tumors? This drug did not cause tumors in Monkey's or Mice, why was that not discussed at all?
4. Why did Eric Colman make public statements after Vivus' Qnexa review like
"When you listen to even the 'no' voters, you got the sense a lot of people had a little bit of hesitancy," FDA Deputy Director for Endocrine Products Eric C. Colman, MD, said in a news conference. "They were not strongly against the drug but had lingering concerns that made them vote 'no.'"
“I was a little surprised that the vote went as it did,” said Eric Colman, the deputy director of the FDA Division of Metabolism and Endocrinology Products, in a press briefing after the meeting. He declined to elaborate.
Is this legal or is it violation of code of conduct?
5. Can FDA personnel play scare tactics by making intimidating statements like
"your name would be forever attached to a drug that you helped approve and then recalled"
So does this mean Eric Colman thought this drug would be recalled if approved? On what basis? scientific or non-scientific?
6. When FDA is the final authority to approve or deny why would panelists names be of such an importance?
7. Last but not the least, how is it that one nanosecond after FDA briefing docs are made public the analysts and MSM have articles up on line and ready to go? Did they take a speed reading class? And, more to the point: why did they have short positions as of about a month ago, before there was any real news to trade on?
Were the documents leaked ahead of time?
Meridia; a drug that is much less efficacious and actually doesn't even meet FDA' 2007 guidelines and has lot more side effects was reviewed by pretty much the same panel and surprisingly tumors were not the topic of discussion. Meridia is pulled out of Europe for its safety concerns, why is it still available in the US market? It is my understanding that any drug can be dangerous at a toxic dose so not sure why that is an issue with Lorqess. Denying a novel compound which improved life style,controlled sugar levels, controlled LDL and met FDA efficacy and safety guidelines is a mistake that should be avoided, I plead you and FDA to review this matter as it deserves utmost attention.
Note: Lorqess met both efficacy and safety benchmarks, Valvular issues were ruled out in human trails.
I'd also like you to investigate the events and I hope you take necessary action to prevent any unprofessional conduct of any FDA employee.
Full disclosure: I have a small LONG position in ARNA but that doesn't make this letter invalid by any means.
Sincerely,
Versoljobs
To: margaret.hamburg@fda.hhs.gov CC: mary.parks@fda.hhs.gov; eric.colman@fda.hhs.gov; curtis.rosebraugh@fda.hhs.gov; john.jenkins@fda.hhs.gov; janet.woodcock@fda.hhs.gov; mary.kremzner@fda.hhs.gov; cderombudsman@fda.hhs.gov; Lynn@cswd.org; Miriam@cswd.org; paffairs@oig.hhs.gov; president@messages.whitehouse.gov; info@messages.whitehouse.gov; karin.nelson@med.va.gov; info@obesityaction.org; jpratt@obesity.org; fdea@obesity.org; hendersj@wou.edu; info@healthadvocate.com; editors@medicalnewstoday.com; walter@obesitylaw.com; kelley@obesitylaw.com; info@nyccah.org; glennbeck@foxnews.com; cavuto@foxnews.com; ontherecord@foxnews.com; sanjay.gupta@turner.com; dnllpz33@gmail.com
This is a comment by fellow Yahoo MB'er
ReplyDeleteFreezingpoint273 Wrote:
Versol, I read your posts in respect to the email to the FDA. I agree with your course of action(i.e sending this email) however I would like to make two recommendations:
1) Following the email a signed registered letter needs to be sent to all the recipients.
2) ENsure you get the receipt acknowlegements
3)In order to have traction you need the support of some Govt reps. If you recall the issues with DNDN there were 2 congressmen who were also actively corresponding and raising awareness on the DNDN issue. Political support is essential in these cases or else the FDA will not give such emails/letters much weighting.
Please keep us posted on any developments.
Great job, thanks for getting the word out on this important issue!
ReplyDeleteOffice of the Attorney General
ReplyDelete455 Golden Gate, Suite 11000
San Francisco, CA 94102-7004
Phone: (415) 703-5500
Dear Mr. Brown
Attached is a letter that I sent to Dr. Margaret Hamburg, Commissioner of the FDA regarding Arena Pharmaceuticals and their recent FDA panel review meeting on 9/16/2010 for their anti-obesity drug Lorqess for which they are seeking FDA approval.
As the Attorney General for the State of California, I think that you or your office should look into this matter for the following reasons:
1. Arena Pharmaceuticals is a California based company and with Lorqess approval, it would have allowed Arena to create much needed jobs and in addition to generate taxable income.
2. It appears Arena withheld information on the rat study data that could have been relevant to Arena’s investors. Arena alleges that they discussed this data with the FDA, the FDA indicated that the data was not relevant to humans and to continue with their phase III human studies.
3. But at the review meeting for Lorqess, the meeting was dominated by the cancer in rat study information, but the FDA failed to have a Oncologist, Toxicologist and Carcinogenic experts on the panel that would fully understand these studies. A number of the panel members were confused and in my opinion, made wrong vote decisions based on this confusion.
4. In addition, the FDA person directing this meeting – Eric Colman acted as “Judge and Jury” in this meeting and acted in a very unprofessional and unethical manner towards Arena. These panel meetings are taped, so you or a member of your staff can see for yourself.
The panel voted 9-5 against recommending Lorqess for approval but I have reviewed their comments for their votes and if the panel makeup had the noted specialists from above that should have been on the panel, I believe the vote would have been 10-4 or 11-3 in favor of approval. There also was a damaging statement that was made by Eric Colman prior to the vote that should be questioned.
I certainly understand that investing in equities incurs a certain level of risk. I as well as probably thousands of Californians made this investment after doing thorough due diligence. I knew nothing of the cancer in rats study until the briefing documents were released on 9/14/2010 but apparently the documents were leaked since the stock price dropped like a rock right from the opening bell. I blame both Arena and the FDA for this. But to be fair to Arena, the cancer in the rats was likely caused because the rats were receiving extremely large dosages of the medication. In addition, Arena met the guidelines established by the FDA that show a greater than 25-fold safety margin, thus there is no cancer danger to humans. There are over 8000 human patients in the phase III studies and none of them has developed any signs of cancer.
It is still up to the FDA to make the approval decision. The PDUFA date for that decision is October 22nd, 2010. The corrective action that I think is the solution is for the FDA to redo the panel meeting but with a different panel makeup as indicated. In addition, they should have Eric Colman excuse himself from further involvement with the Lorqess approval process.
As I indicated on the YMB, I sent a letter to Ms. Hamburg and to Attorney General of California - Jerry Brown today by registered letter. I will also send letters to Senators Boxer, Whitman and my Congressman.
ReplyDelete