Link: http://www.investorvillage.com/smbd.asp?mb=633&mn=9444&pt=msg&mid=9801323
Improper influence of former Director taints FDA analysis of Lorqess
Dear Ms. Behr and Ms. Kremzer,
Re: FDA employee improperly influenced by a former FDA director with a financial interest
Please consider this letter the lodging of a formal complaint with your office and request for remedy.
Complaint
I allege that Fred K. Alavi an FDA employee has been improperly influenced by a former FDA director Dr. David Orloff. The result of the influence has to all appearances tainted Dr. Alavi’s work.
I cite as evidence Alavi’s unprofessional and unscientific contribution to the FDA Briefing document (UCM225631.pdf) for an FDA Advisory Committee meeting held Sept 16, 2010 on to consider the weight loss drug Lorqess.
To wit:
1. Arena Pharceuticals’s obesity candidate, Lorqess (lorcaserin) is widely acknowledged potential competitor of Vivus. Inc’s obesity drug candidate, Qnexa
2 Dr. David Orloff has a financial interest in Vivus. Inc’s obesity drug Qnexa because he oversaw the trials of this drug:
http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933
“MOUNTAIN VIEW, Calif., Sept 09, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- VIVUS, Inc. (Nasdaq: VVUS) today announced positive results from two final, phase 3 pivotal 56-week studies, EQUIP (OB-302) and CONQUER (OB-303), evaluating the safety and efficacy of Qnexa(TM), an investigational drug, in more than 3,750 patients across 93 sites……Wilson added, "We are proud of the results of our Qnexa phase 3 program, and I would like to thank Dr. Thomas Najarian, the inventor of Qnexa, the entire development team at VIVUS, Dr. David Orloff and his staff at Medpace, the clinical research organization that managed these studies, and the clinical investigators and patients who participated in the Qnexa clinical trials."…
3. Immediately proceeding Medpace, Orlof was a FDA director in the very same division that is currently overseeing the review of drugs to treat metabolic and endocrine disorders – including the obesity candidates Qnexa and Lorqess.
http://www.medicalnewstoday.com/articles/34644.php
“David Orloff, an FDA division director who oversees the review of drugs to treat metabolic and endocrine disorders, has announced plans to leave the agency and join Medpace, a contract research firm based in Cincinnati that runs clinical trials, the New York Times reports.
4. During the time of Orloff’s directorship in the very same metabolic and endocrine disorders division, one Fred Alavi was a subordinate reviewer under Orloff:
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_02_04-FDA-ClinPharm-Toxicology.pdf
“….Pharmacology/Toxicology Review And Evaluation…Nda Number: 21-868…
Pharm/Tox Reviewer: Fred Alavi, Ph.D.
Pharm/Tox Supervisor: Jeri Elhage, Ph.D.
Division Director: David Orloff, Md…”
5. The linchpin of the FDA’s rejection of Lorqess are analyses of trial results conducted by Fred Alavi, that I allege are faulty. See the following:
6. Dr. Alavi, authored the subsection, of the FDA Briefing document for the meeting to consider Lorqess (UCM225631.pdf) , entitled “Genoxicity and Carcinogenicity Assess ment for Lorcaserin”.
Page five of that subsection is entitled: “Rat Carcinogenicity Study.” In that subsection the word “carcinogenicity” appears at least four times. Yet the reader of this document discovers that benign, repeat benign, tumor data has been included. Namely, Table 4 of this subsection reports the occurrence of benign fibroademomas even though it is entitled, “Incidence of lorcaserin-induced tumors in the 2 year rat carcinogenicity study.”
Even worse, the occurrence of these benign tumors have been “combined” with the occurrence of malignant tumors to fabricate an ostensible statistically significance (“SS”) for carcinogenicity. It is only valid to group benign and malignant neoplasms of a particular histogenesis when malignancy is seen as a progression from the benign tumor. Cf. Preclinical Development Handbook Toxicology 2008 John Wiley & Sons New Jersey Carcinogenicity Studies 424- 455. And “ malignant transformations in the epithelial components of fibroadenomas are generally considered rare. The incidence of a carcinoma evolving within a fibroadenoma was reported to be 0.002% to 0.0125%."(Ron Greenberg, MD,1 Yehuda Skornick, MD,1 and Ofer Kaplan, MD: Management of Breast Fibroadenomas, J Gen Intern Med. 1998 September; 13(9): 640–645).
The incorporation of non-progressing benign tumor results in a conclusion about carcinogenicity is incorrect, unscientific and ridiculous.
6. Dr. Alavi furthermore “cooked the books” against Lorqess by disregarding monkey brain-to-plasma ratio partitioning data to ascertain brain concentrations of Lorqess. He instead compared plasma drug levels between rats and humans. The safety margin using the primate brain-to-plasma model is 17x the clinical dose, whereas the rat plasma-to-plasma model is 5x the clinical dose. This flies in the face of common sense – it is improper and deceptive to use a comparison between rodents and humans when a comparison between primates and human s is available.
Furthermore, species difference aside, the traditional in vivo brain-to-plasma partitioning ratio is the method of choice by CNS drug discovery programs. The vast majority of CNS drugs were developed using this method and it is still the gold standard in the drug discovery industry. The method proposed by Dr. Alavi was to use plasma-to-plasma levels to determine the margin of safety, which is widely reported as flawed in scientific literature. There is strong evidence that this is an unreliable method due to marked intraspecies variation in drug levels. Thus, the plasma-to-plasma level determination used by Dr. Alavi is an unaccepted method for margin of safety levels.
8. Dr. Alavi’s failure to use monkeys as the animal model is contrary to science, common sense and longtime industry practice. He founds his disregard on the queasy-sand circular logic that there was no human data. The vast majority of CNS drug discovery programs use animal models, precisely because there rarely are any human brain data -- and because of the proven inter-species conservation of the blood-brain barrier which is the primary obstacle for drug penetration into the CNS. Furthermore, several studies have confirmed that brain tissue binding is comparable across species. It is idiocy to assert genetic rodent neurobiology should be favored for comparative determination over that of non-human primates. Dr. Alavi ignores grade school science that monkeys are much more similar to humans than rats. Duh. Monkeys are the primary animal species used in drug metabolism studies, in HIV and vaccination studies. To disregard their use is unfounded scientifically.
Remedy requested
My request for remedy is that any and all requirements in the FDA’s Complete Response Letter issued to Arena Pharmaceuticals on Oct 23, 2010 that are founded on the mistaken and tainted Alavi analyses be waived and retracted.
Sincerely Yours.
Re: FDA employee improperly influenced by a former FDA director with a financial interest
Please consider this letter the lodging of a formal complaint with your office and request for remedy.
Complaint
I allege that Fred K. Alavi an FDA employee has been improperly influenced by a former FDA director Dr. David Orloff. The result of the influence has to all appearances tainted Dr. Alavi’s work.
I cite as evidence Alavi’s unprofessional and unscientific contribution to the FDA Briefing document (UCM225631.pdf) for an FDA Advisory Committee meeting held Sept 16, 2010 on to consider the weight loss drug Lorqess.
To wit:
1. Arena Pharceuticals’s obesity candidate, Lorqess (lorcaserin) is widely acknowledged potential competitor of Vivus. Inc’s obesity drug candidate, Qnexa
2 Dr. David Orloff has a financial interest in Vivus. Inc’s obesity drug Qnexa because he oversaw the trials of this drug:
http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933
“MOUNTAIN VIEW, Calif., Sept 09, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- VIVUS, Inc. (Nasdaq: VVUS) today announced positive results from two final, phase 3 pivotal 56-week studies, EQUIP (OB-302) and CONQUER (OB-303), evaluating the safety and efficacy of Qnexa(TM), an investigational drug, in more than 3,750 patients across 93 sites……Wilson added, "We are proud of the results of our Qnexa phase 3 program, and I would like to thank Dr. Thomas Najarian, the inventor of Qnexa, the entire development team at VIVUS, Dr. David Orloff and his staff at Medpace, the clinical research organization that managed these studies, and the clinical investigators and patients who participated in the Qnexa clinical trials."…
3. Immediately proceeding Medpace, Orlof was a FDA director in the very same division that is currently overseeing the review of drugs to treat metabolic and endocrine disorders – including the obesity candidates Qnexa and Lorqess.
http://www.medicalnewstoday.com/articles/34644.php
“David Orloff, an FDA division director who oversees the review of drugs to treat metabolic and endocrine disorders, has announced plans to leave the agency and join Medpace, a contract research firm based in Cincinnati that runs clinical trials, the New York Times reports.
4. During the time of Orloff’s directorship in the very same metabolic and endocrine disorders division, one Fred Alavi was a subordinate reviewer under Orloff:
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_02_04-FDA-ClinPharm-Toxicology.pdf
“….Pharmacology/Toxicology Review And Evaluation…Nda Number: 21-868…
Pharm/Tox Reviewer: Fred Alavi, Ph.D.
Pharm/Tox Supervisor: Jeri Elhage, Ph.D.
Division Director: David Orloff, Md…”
5. The linchpin of the FDA’s rejection of Lorqess are analyses of trial results conducted by Fred Alavi, that I allege are faulty. See the following:
6. Dr. Alavi, authored the subsection, of the FDA Briefing document for the meeting to consider Lorqess (UCM225631.pdf) , entitled “Genoxicity and Carcinogenicity Assess ment for Lorcaserin”.
Page five of that subsection is entitled: “Rat Carcinogenicity Study.” In that subsection the word “carcinogenicity” appears at least four times. Yet the reader of this document discovers that benign, repeat benign, tumor data has been included. Namely, Table 4 of this subsection reports the occurrence of benign fibroademomas even though it is entitled, “Incidence of lorcaserin-induced tumors in the 2 year rat carcinogenicity study.”
Even worse, the occurrence of these benign tumors have been “combined” with the occurrence of malignant tumors to fabricate an ostensible statistically significance (“SS”) for carcinogenicity. It is only valid to group benign and malignant neoplasms of a particular histogenesis when malignancy is seen as a progression from the benign tumor. Cf. Preclinical Development Handbook Toxicology 2008 John Wiley & Sons New Jersey Carcinogenicity Studies 424- 455. And “ malignant transformations in the epithelial components of fibroadenomas are generally considered rare. The incidence of a carcinoma evolving within a fibroadenoma was reported to be 0.002% to 0.0125%."(Ron Greenberg, MD,1 Yehuda Skornick, MD,1 and Ofer Kaplan, MD: Management of Breast Fibroadenomas, J Gen Intern Med. 1998 September; 13(9): 640–645).
The incorporation of non-progressing benign tumor results in a conclusion about carcinogenicity is incorrect, unscientific and ridiculous.
6. Dr. Alavi furthermore “cooked the books” against Lorqess by disregarding monkey brain-to-plasma ratio partitioning data to ascertain brain concentrations of Lorqess. He instead compared plasma drug levels between rats and humans. The safety margin using the primate brain-to-plasma model is 17x the clinical dose, whereas the rat plasma-to-plasma model is 5x the clinical dose. This flies in the face of common sense – it is improper and deceptive to use a comparison between rodents and humans when a comparison between primates and human s is available.
Furthermore, species difference aside, the traditional in vivo brain-to-plasma partitioning ratio is the method of choice by CNS drug discovery programs. The vast majority of CNS drugs were developed using this method and it is still the gold standard in the drug discovery industry. The method proposed by Dr. Alavi was to use plasma-to-plasma levels to determine the margin of safety, which is widely reported as flawed in scientific literature. There is strong evidence that this is an unreliable method due to marked intraspecies variation in drug levels. Thus, the plasma-to-plasma level determination used by Dr. Alavi is an unaccepted method for margin of safety levels.
8. Dr. Alavi’s failure to use monkeys as the animal model is contrary to science, common sense and longtime industry practice. He founds his disregard on the queasy-sand circular logic that there was no human data. The vast majority of CNS drug discovery programs use animal models, precisely because there rarely are any human brain data -- and because of the proven inter-species conservation of the blood-brain barrier which is the primary obstacle for drug penetration into the CNS. Furthermore, several studies have confirmed that brain tissue binding is comparable across species. It is idiocy to assert genetic rodent neurobiology should be favored for comparative determination over that of non-human primates. Dr. Alavi ignores grade school science that monkeys are much more similar to humans than rats. Duh. Monkeys are the primary animal species used in drug metabolism studies, in HIV and vaccination studies. To disregard their use is unfounded scientifically.
Remedy requested
My request for remedy is that any and all requirements in the FDA’s Complete Response Letter issued to Arena Pharmaceuticals on Oct 23, 2010 that are founded on the mistaken and tainted Alavi analyses be waived and retracted.
Sincerely Yours.
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