Dr. Daniel's Letter to the FDA on tumor data

October 6, 2010


Margaret Hamburg, M.D.
Commissioner, Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993

Dear Dr. Hamburg,

We are writing as concerned physicians and scientists faced daily with the obesity crisis to request that the FDA conducts an internal review of the science and procedures behind the advisory committee meeting held on during 16th of September 2010 to review Lorcaserin Hydrochloride (APD356), a novel selective compound developed by Arena Pharmaceuticals, Inc for treating obese patients. The committee voted 9 to 5 against recommending that FDA approve 10-mg, BID, orally administered Lorcaserin for chronic human use. The negative vote was despite the evidence that Lorcaserin clearly met one of two of the FDA's required pre-established 2007 criteria for obesity drug efficacy (From Guidance for Industry: Developing Products For Weight Management, Clinical Assessment of Weight Management Products in Adult Patients, Section IV, B.3c). As a result, it seems likely that a promising new compound that could help obese people lose weight will not be approved for use by those who urgently require new and effective medicines. Among the obese people who took Lorcaserin in the Phase III trial, 2 of 3 lost 26 pounds within a year[1] while 1 in 4 shed 35 pounds. In our opinion, which is shared by many medical professionals, these numbers are far more important to the real world use of Lorcaserin than any measures based on "average" weight loss across the entire study group. In spite of the proven documented categorical weight loss, overall health, and quality of life benefits, the advisory committee review centered almost solely on simple net averages. Lorcaserin could be a life-changing drug for a significant subset of those treated with it, while those who do not respond as well under medical supervision would surely discontinue its use rapidly.

The meeting transcript shows that the most important influence on the panel members' negative votes was the concern raised by the FDA that Lorcaserin causes various cancers in rats and might do so in humans. These perceived problems surfaced in a briefing document in the introductory Memorandum prepared by Dr. Eric Colman and released to the public on 14th of September 2010. We believe the issue of Lorcaserin causing cancer in rats has been misinterpreted, a view we know is shared by other physicians and drug development scientists with whom we have discussed this issue.

FDA's own guidance on 2-year carcinogenicity studies states: "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." (See Appendix for more detailed statements derived from FDA documents).

The above statement is highly relevant in light of the facts about the Lorcaserin 2-year rat carcinogenicity studies that I will now review. In the nonclinical 2-year carcinogenicity study, SD female rats were given an oral dose of Lorcaserin that was up to 82-fold the proposed therapeutic dose for human use, per mean blood plasma AUC levels.



Table 3: Multiples of clinical exposure to lorcaserin achieved in 2yr rat study -
104-week Rat Carcinogenicity Study

Dose, mg/kg
Males
Females
10 (LD)
5x
7x
30 (MD)
17x
24x
100 (HD)
55x
82x
Exposure multiples calculated as AUC exposure in rats divided by average AUC exposure of the clinical dose of lorcaserin, 10mg BID, 1.02 ug*h/ml AUC


Female rats were therefore dosed with Lorcaserin at significantly above the 25-fold ICH limit dose referred to above, in respect to mean plasma AUC concentrations. (FDA’s own May 2002 ‘Guidelines to Industry’ states “the highest dose to be included in a carcinogenicity study should be based on one of the ICH endpoints (referencing “Toxicity, Dose-Limiting PD Effects, Exposures 25 times Human AUC, Saturation of Absorption, Maximum Feasible Dose (MFD), or Limit Dose”). The over-dosing (again, 82-fold above the proposed human dose) resulted in the high dose group receiving extremely toxic levels of the compound. The following statement from Phippus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus, (1493-1541): "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy" (Klaassen 2001) still guides toxicologists today in the development of modern pharmaceutical drugs.

We believe that an excess number of rat deaths in the ultra high-dose Lorcaserin group were attributable to toxicity, and not to tumor growth. Of note is that poisonous doses of Lorcaserin were not used in the 2-year carcinogenicity study carried out in male and female mice, and no mammary adenocarcinomas were found in that species. Furthermore, no statistically significant differences in mammary adenocarcinoma incidence, compared to controls, were detected in male rats given Lorcaserin at doses of up to 100 mg/kg/day (55-fold higher than the human therapeutic dose). Again, the FDA's own guidelines (see Appendix A) are highly relevant, and yet not one panel member or FDA official brought them up for discussion at the advisory committee meeting!

The interpretation of the carcinogenicity data in the FDA briefing document also needs to be reviewed.  A Memorandum in the opening section provides an introductory overview of the efficacy and safety of Lorcaserin to the advisory committee members (see "Safety of Lorcaserin"; 6th paragraph; Malignancies in Rats, September 16, 2010 FDA Briefing Document, Lorcaserin Hydrochloride (APD356)). There, Dr. Eric Colman states:  "An excess number of malignant tumors developed in female rats with Lorcaserin at doses within 7-fold of the proposed clinical dose of 10mg BID." Dr. Colman’s statement implies that, statistically, the malignant tumor incidence in the 10mg/kg/day female SD rat group (7x dose group) was significantly different from control. His statement is, however, factually incorrect. For reasons we will expand upon below, the only “malignant mammary tumors” observed in the study were mammary adenocarcinoma lesions, and there was no statistically significant excess of these tumors at the dose reported (see Table 4 below, where NS = Not Significant).  In simple words, the incidence of malignant adenocarcinoma tumors identified in the 10 mg/kg/day female group was no different to the 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 normal malignant mammary tumor incidence reported in the untreated control female rats. Only at 100 mg/kg/day is there a statistically significant increase in adenocarcinomas, but this Lorcaserin dose is 82-fold that intended for human use.

Female rats
Lorcaserin dose, mg/kg/day
Incidence of tumors
Control
10 (7-fold)
30 (24-fold)
100 (82-fold)
Mammary
adenocarcinoma
28
34 NS
35 NS
60 SS
fibroadenoma
20
47 SS
53 SS
45 SS
combined
40
56 SS
61 SS
70 SS

This table is Table 4, taken from the September 16, 2010 FDA Briefing Document, Lorcaserin Hydrochloride (APD356).

Regarding tumors in the male rats, Dr. Colman stated: “Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose.” However, only two tumors were in fact seen at the reported dose level, a number that was far from statistically significant (again, see Table 4)

Male rats
Lorcaserin dose, mg/kg/day
Incidence of tumors
Control
10 (5-fold)
30 (17-fold)
100 (55-fold)
Mammary
adenocarcinoma
0
0
2
2 NS
fibroadenoma
0
1
4 NS
6 NS
combined
0
1
6 SS
8 SS

In Table 4, the breast tumor incidence only becomes statistically different from that in untreated control rats (male or female) if the different tumors are combined, but this is not a valid procedure because one of the tumor types is malignant (adenocarcinoma), the other benign (fibroadenoma). Understanding this point is of critical importance to how the rat carcinogenicity data are interpreted.

In the FDA briefing document section entitled: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin” (4th paragraph; Mammary Tumors), Dr. Alavi (FDA’s nonclinical pharmacology/toxicity presenter) makes the following statement: “The FDA’s risk assessment is based on the combined incidence of mammary fibroadenoma and adenocarcinoma, and is not substantially swayed by the argument that statistically significant malignant adenocarcinoma was confined to high dose females.” Dr. Alavi has made an incorrect presumption. While it is true that benign and malignant tumors are sometimes combined, this procedure should only be done if the following criterion is fulfilled: "Benign and malignant neoplasms of a particular histogenesis (cell-type origin) are often grouped because the one is seen as a progression from the other" (Gad 2008, Carcinogenicity Studies 424- 455). First, fibroadenoma and adenocarcinoma arise from cell types with different histogenesis. Adenocarcinomas are classified under the epithelial histotype, fibroadenomas under the epithelial-stromal histotype. From the classification listed below (Table A), 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).  In the first listed reference, Russo clearly states on page 245 that the rat model of tumorigensis closely mimics human breast tumor development. This mammary tumor classification system is universally accepted by Board-certified veterinary pathologists, who commonly investigate the comparative tumor tissue nature of human/animal carcinogenic lesions. Perhaps Dr. Alavi and Dr. Colman are unaware of this?

Table A: Classification of Neoplastic and Non-neoplastic Lesions of the Rat Mammary Gland with Comparisons to Human Lesions (Russo et al. 1990, Table 9, p. 267)

RAT LESION
CORRESPONDING HUMAN LESION
Benign Epithelial Neoplasms
Adenoma

Papilloma, adenoma

Malignant Epithelial Neoplasms
Ductal Carcinoma

Ductal carcinoma
Ductal carcinoma in-situ
Lobular carcinoma
Paget’s disease of the nipple

Benign Stromal Neoplasms
Fibroma


Fibroma

Malignant Stromal Neoplama
Fibrosacrcoma


Fibrosarcoma

Benign Epithelial-Stromal Neoplasms
Fibroadenoma


Fibroadenoma
Cytosarcoma
Malignant Epithelial-Stromal Neoplasms
*Carcinosarcoma

Carcinosarcoma
*This malignant mammary tumor was not observed in rats dosed with Lorcaserin Hydrochloride up to 82-fold the proposed human therapeutic dose (per mean AUC basis).

It is also the case that “benign fibroadenomas and adenomas that occur in rats closely resemble the human benign tumors” (Russo et al, 1990, p. 262). It can be emphatically concluded that fibroadenomas rarely progress to adenocarcinoma in the rat (Boorman and Everitt 2006) and hence that the rat data have no significant relevance to humans. A study that investigated whether rat mammary fibroadenomas transform to mammary adenocarcinoma by examining the gene expression of the two tumor types and comparing them to mammary glands in the same developmental state stated: “We conclude that in tumours examined here, no progression to adenocarcinoma is likely” (Marxfield, Staedtler, and Hareleman 2006).  On this point, we note that in women “The risk of subsequent breast cancer is slightly elevated only if the fibroadenoma is complex, if there is adjacent proliferative disease or if there is a family history of breast cancer. For the majority of women with simple fibroadenomas, there is no increased risk of developing breast cancer" (London, et al. 1992).

            It is clear from the above discussion that we are dealing with two distinctly different tumors, and that Dr. Alavi’s pooling of the two data sets is scientifically inappropriate. Dr. Alavi has also compounded his initial error, as follows. In discussing the fatalities from these tumors, he posited the possible risk to humans from these tumors: “However, because the excess mortality observed with lorcaserin was due to drug-induced tumors rather than other toxicity, exposure achieved in the rats did not exceed a maximum tolerated dose, and the relevance of the tumors to human risk cannot be dismissed based on that argument” in the section entitled: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin”(3rd paragraph; Survival)  In this statement Dr. Alavi intimated that human risk with respect to mortality was due to the fibroadenomas and adenocarcinomas.  He went on to conclude: “Confining the analysis to the final incidence of mammary tumors without consideration of tumor-related mortality is not justified. Among the deaths attributed to mammary tumors, approximately 1/15, 6/31, 14/43 and 10/68 deaths were attributed to fibroadenoma in the control, LD, MD and HD female rats, respectively, suggesting that fibroadenoma as well as adenocarcinoma were fatal” in the section entitled: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin”(4th paragraph; Mammary Tumors).  This statement is misleading because he does not make a distinction on the cause of death between benign mammary fibroadenomas and malignant mammary adenocarcinomas.  Malignant tumors cause death of the host by their properties of unrestricted growth, invasive behavior (capable of invading adjacent tissues and organs), and potential for metastasis.  Benign tumors have none of these properties.  Mammary fibroadenomas cause death due to a mass effect, because they can increase in size 10-fold and can encompass up to half the body weight of the rat.  Because of their large size they can obstruct other organs, inhibit its mobility, and impede the rat’s ability to feed.  Other documented causes of death from mammary fibroadenomas include ulceration from excessive growth, which can lead to fatal hemorrhage and septicemia secondary to necrosis of the tumor ((Boorman et al, 2006).  In a report consisting of 20 rat and 20 mouse carcinogenicity studies intended to establish a general profile of tumors in CD-1 rats and SD rats (the same rats used in the Lorcaserin Carcinogenicity Studies), the second most common cause of death of rats was fibroadenomas, and it was stated that” it is important to determine whether tumors are incidental or fatal in nature. Some deaths from mammary tumors were classified as fatal, as the size and condition of the tumors were factors in the decision to euthanatize the animal for humane reasons” (Son and Gopinath 2004). 

The central point here is that Dr. Alavi misrepresented the data by not emphasizing that rat fatalities from benign fibroadenomas would not translate as a risk to humans.  Human females do not die from fibroadenomas.  It is inconceivable to postulate that a human female would allow a breast fibroadenoma to increase to an extent where it constituted up to half of her body weight. By combining benign mammary fibroadenomas and malignant adenocarcinomas to reach a statistically significant risk, and concluding that these results can be relevant to the risk of humans acquiring cancer, Dr. Alavi has distorted the data in a way that is unreasonable and inappropriate.

Our points are not completely new: Cancer expert Dr. Gary Williams, a world renowned pathologist, testified to the advisory panel that the cancers seen in one species of rat did not apply to humans, that breast tissue cancer was not seen in mice, and that cancer was not seen in the in two pivotal Phase 3 clinical studies. Dr. Williams also pointed out that a clear distinction must be made between fibroadenomas (benign) and adenocarcinomas (malignant) of the breast. His testimony was either not understood by the panel members, or it was ignored. None of the panel members was an expert in human and rat comparative carcinogenesis; the panel therefore lacked the specialist knowledge required to evaluate and interpret the mammary tumors in female SD rats. As a result, what I believe should have been a non-issue weighed heavily on the minds of the panel members, and on various people who provided opinions to the panel during the relevant phase of the meeting. Several FDA regulatory officials, and at least 9 voting members of the panel, were clearly uncertain, and perhaps even confused, about the clinical relevance of the rat tumor data. Overall, the fear of cancer scared several presenters and influenced the panel's vote significantly. If the FDA officials were so concerned about rat deaths due to mammary tumors, then why was the ongoing Phase 3 study not placed on clinical hold within the Agency’s mandatory reporting time of no more than 15 days for observed deaths and study-related serious adverse events (see Appendix B). If rat deaths due to breast cancer and these rodent findings were acknowledged as life threatening and serious by the Carcinogenicity Assessment Committee (CAC), the rat and human Phase 3 should have been immediately terminated.  Thus, I believe it was obvious to CAC that such findings were not considered to be serious and life threatening to the human clinical trial participants.
  
We request that the FDA brings in well-qualified outside experts, including a board-certified veterinary pathologist and/or toxicologist with drug development expertise, to review all the nonclinical and clinical data on Lorcaserin and its association with cancer before deciding on October 22nd whether or not to approve a highly important drug that is urgently needed to combat the nation's obesity crisis. Physicians and patients badly need additional therapeutic options. We fully understand that one of the prime functions of the FDA relates to drug safety. Quite where the line should be drawn on the risk/benefit ratio is often difficult; it can even be subjective. But it is important that, when anticipated safety issues are presented, they be genuine ones based on sound science. On this occasion, we believe the FDA has erred in its briefing document, and in the way its own clinical and nonclinical officials guided the deliberations of the panel members. We urge you to review what happened before and during the advisory panel meeting of September 16, 2010, including the actions of FDA employees involved in the process.

We also encourage you to consider whether the FDA has developed an institutional bias against weight loss drugs because of the perception that they might be widely used as “vanity drugs”, rather than as specialist medical tools to be taken under the close supervision of a physician. While it is certainly possible that any licensed drug might be used inappropriately, that is not necessarily a valid reason to deprive those who truly need pharmaceutical assistance in addressing the serious health problem of obesity.

Although this letter is addressed to you, Dr. Hamburg, we recommend that you consult Dr. David Jacobson-Kram (Office of New Drugs, CDER) on this issue.  He is a highly experienced, board-certified toxicologist employed by the FDA. Accordingly, we have cc-ed Dr. Jacobson-Kram. We have also sent copies of the letter to our Congressional representatives.

We make the disclosure that we own stock in Arena Pharmaceuticals, Inc.  We sincerely believe, however, that we are writing to you because there is a world-wide obesity crisis and new obesity drugare urgently needed. We thank you for taking time to evaluate whether a fair and impartial and objective evaluation was conducted in the advisory committee meeting held on during 16th of September 2010 to review Lorcaserin Hydrochloride (APD356), a novel selective compound developed by Arena Pharmaceuticals.

Sincerely,


Daniel
Daniel P. Lopez, M.D., F.A.C.O.G.
Department of Obstetrics and Gynecologic Surgery
Southern California Permanente Medical Group
Gardena Medical Offices

Steven
Steven Vig, M.D.
Internal Medicine
Carondelet Medical Group
Tuscon, AZ

Rajesh Patel, Ph.D.


CC via Certified Mail, Return Receipt Requested


 
David Jacobson-Kram, Ph.D., D.A.B.T.
Associate Director of Pharmacology and Toxicology
Office of New Drugs
Center for Drug Evaluation and Research
U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993

President of the United States Barrack Obama
The White House
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United States Surgeon General Dr. Regina M. Benjamin
Office of the Surgeon General
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Room 18-66
Rockville, MD  20857

Mary  Kremzner
CDER Ombudsman Central Document Room
FDA/Center for Drug Evaluation and Research
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U.S. Senator Chuck Grassley R. IA
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U.S. Senator Chuck Grassley R. IA
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101 1st Street , SE
Cedar Rapids, IA  52401
Representative John Dingell  D. MI
2328 Rayburn House Office Building
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United States Attorney General Eric H. Holder
U.S. Department of Justice
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Secretary Kathleen Sebelius
Department of Health and Human Services
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Captain Mary Kremzner
CDER Ombudsman – FDA
Food and Drug Administration
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Joshua Sharfstein
Principal Deputy Commissioner – FDA
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WO1 - Room 220
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Janet Woodcock
CDER Director – FDA
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Curtis Rosebraugh
CDER Office of Drug Evaluation – FDA
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Mary Parks
CDER Division of Metabolism and Endocrinology Products – FDA
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John Jenkins
CDER Director of New Drugs – FDA
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Rep. Darrell Issa
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Rep. Darrell Issa
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Senator Alex Padilla
District SD20
State Capitol, Room 4038
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Assemblymember Felipe Fuentes
District AD39
State Capitol
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Attorney General Edmund G. Brown, Jr.
Attorney General’s Office
California Department of Justice
Attn: Public Inquiry Unit
P.O. Box 944255 Sacramento, CA 94244-2550

CC Advisory Committee Members Present at the 16th of September 2010 Review of Lorcaserin Hydrochloride (APD356)

Sanjay Kaul, M.D.
Cedars-Sinai Medical Center
Division of Cardiology – Room 5314
PO Box 48750
Los Angeles, CA 90048-0750

Michael Proschan
Office of Biostatistics Research
National Heart, Lung, and Blood Institute
II Rockledge Center
6701 Rockledge Drive, MSC 7938
Bethesda, Maryland 20892-7938

Allison B. Goldfine, M.D.
Joslin Diabetes Center
One Joslin Place
Boston, MA 02215

Eric Felner, M.D.
2015 Uppergate Dr.
Atlanta, GA 30322

Dr. Lamont G. Weide, M.D.
2310 Holmes Street Suite 800
Kansas City, MO 64108

Abraham Thomas, M.D., M.P.H.
Division of Endocrinology
3031 West Grand Blvd
Suite 800
Detroit, Michigan 48202

Melanie G. Coffin
1102 Lewis Avenue
Rockville, MD 20851

Edward W. Gregg, Ph.D.
Division of Diabetes Translation Centers
For Disease Control and Prevention
4770 Buford Highway
N.E. Mailstop K-10
Atlanta GA 30341

Dr. Heidi Connolly
Mayo Clinic
200 1st Street South West
Rochester, MN 55905

Jessica Henderson
Associate Professor Health and Physical Education
New PE, Room 208
Western Oregon University
345 N. Monmouth Ave.
Monmouth, Oregon 97361

Pamela S. Douglas, M.D.
Department of Medicine
Division of Cardiology
P.O Box 17969
7022 North Pavilion
Durham, NC 27715

Katherine M. Flegal, Ph.D.
National Center for Health Statistics
Centers for Disease Control and Prevention
3311 Toledo Rd.
Room 4315
Hyattsville, MD 20782

Jacqueline S. Gardener, Ph.D., M.P.H.
Department of Pharmacy
University of Washington
1959 NE Pacific Street
Health Sciences Building, Room H-375
Box 357630
Seattle, Washington 88195-7630

 




Appendix: Statements derived from FDA documents
A) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074919.pdf

Taken from Guidance for Industry: S1C (R2) Dose Selection for Carcinogenicity Studies, page 4, Section C. (Pharmacokinetic Endpoints in High Dose Selection (1.3)

“It is recognized that the doses administered to different species might not correspond to tissue concentrations because of different metabolic and excretory patterns. Comparability of systemic exposure is better assessed by blood concentrations of parent drug and metabolites than by administered dose. The unbound drug in plasma is thought to be the most relevant indirect measure of tissue concentrations of unbound drug. The AUC is considered the most comprehensive pharmacokinetic endpoint since it takes into account the plasma concentration of the compound and residence time in vivo.”

“There is, as yet, no validated scientific basis for use of comparative drug plasma concentrations in animals and humans for the assessment of carcinogenic risk to humans. However, for the present, and based on an analysis of a database of carcinogenicity studies performed at the MTD, the selection of a high dose for carcinogenicity studies that represents a 25- to-1 exposure ratio of rodent to human plasma AUC of parent compound and/or metabolites is considered pragmatic (Note 3).”

B)
 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=312.32

Excerpt from the citation: CFR 312.32.

“Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification shall be made as soon as possible and in no event later than 15 calendar days after the sponsor's initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological studies shall be submitted in a narrative format) and shall bear prominent identification of its contents, i.e., "IND Safety Report." Each written notification to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND. If FDA determines that additional data are needed, the agency may require further data to be submitted.”



Works Cited

Boorman, G., and J. Everitt. "Neoplastic Disease." In The Laboratory Rat: American College of Laboratory Animal Medicine, edited by M. Suckow, S. Weisbroth and C. Franklin, 502. Toronto: Academic Press, 2006.
Gad, Shane C., ed. Preclinical Development Handbook: Toxicology (Pharmaceutical Development Series). 1st. Wiley Interscience, 2008.
Klaassen, Curtis D. Casarett & Doull's Toxicology: The Basic Science of Poisons. 6th. McGraw-Hill Professional, 2001.
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.
Marxfield, H., F. Staedtler, and J.H. Harelemena. "Gene Expression in Fibroadenomas of the Rat Mammary Gland in Contrast to Spontaneous Adenocarcinomas and Normal Mammary Glands." Experimental Toxicologic Pathology 58, no. 2-3 (2006): 145-150.
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.
Son, W., and C. Gopinath. "Early Occurance of Spontaneous Tumors in CD-1 Mice and Sprage-Dawley Rats." Toxic Pathology 32 (2004): 371-74.


[1] 66.4% of Lorcaserin patients lost at least 5% of their body weight, compared to 32.1% for placebo, and the average weight loss in this responder population was 26 pounds.