Citizens for Lorcaserin

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September 24, 2010

Dear Concerned Citizen,

In its entirety, this is a document that was created by a group of physicians, Ph.D scientists, business professionals and in general, concerned citizens. The present letter summarizes the specific arguments the FDA Advisory Committee (AC) made against the approval of Lorcaserin given on September 16th, 2010, and the following monograph directly refutes these arguments with scientific evidence.

On or before October 22nd, the Food and Drug Administration will decide if Lorcaserin should be approved for market. It is our sincere hope that with the support of other concerned citizens, we can bring to light the misinterpretations and misrepresentations witnessed during the Advisory Committee review on the 16th of September. It should be noted that of the 9 no votes, only two panel members did not cite the issue of tumors in rats as their main concern. This suggests 7 panelists that voted no might have voted yes if the FDA had provided a toxicology or a carcinogenic expert as support for any concerns the panelists might have had regarding the relevance to human subjects. It is clear that these panelists were confused or uncertain what the rat data showed, and therefore voted no, not based on scientific evidence but rather the fear of uncertainty.

Issues other than rat tumors brought to bear during the AC review are also addressed in the monograph below. We believe that the 9-5 vote against Lorcaserin conservatively could have been 9-5 or 10-4 in favor of approval had the FDA provided the appropriate resources for the panelists, which we believe was the charge of the agency.

We believe that the long term effects of this event could result in irreparable damage to the bio-technology and pharmaceutical industry as a whole. The dramatic elevation of concern over rat cancer (as not all tumors are malignant) has prompted Class Action Suits (CAS) against Arena Pharmaceuticals. Clearly these data were adjusted to show significance in cancer occurrence where none existed. If all pharmaceutical and research firms were to release all toxicological results from their pre-clinical or animal studies to the investing community, equity markets in that industry might cease to exist. The public release of a good volume of pre-clinical data would promote general fear and uncertainty which would stifle investments; consequently, smothering advances in medical treatments for society. This is because such toxicity and carcinogenicity studies are designed specifically to show levels at which these toxic events occur. However, these studies are not designed to explain or necessarily discover the mechanism for tumor growth.

A show of support en masse may or may not change the course of events, but we have the privilege and right in our country to stand together and protest when we feel the needs of the commons are not being supported by our government officials. We believe the data show that Lorcaserin is a safe and efficacious drug. Furthermore, we emphasize that millions of people need the help Lorcaserin can provide. For an interview of one of the clinical trial patients, and his overwhelming success in losing weight, please visit;

http://www.youtube.com/watch?v=lcTNh80quS4&feature=related


If you are in agreement with our position, and would like to show your support, please sign the online petition.

Sincerely,

Citizens for Lorcaserin

Please note that the citizens who have signed this letter represent broad diversity professionally, geographically and politically. We are, however, strongly united in our desire defend a just and balanced evaluation in the matter of Lorcaserin. PLEASE ADD YOUR NAME TO THE GROWING LIST OF SUPPORTERS BY SIGNING THIS PETITION.


September 21, 2010

Margaret A. Hamburg
DHHS/FDA/OC
The U.S. Department of Health and Human Services
200 Independence Avenue, S.W.
Washington, D.C. 20201

Re: American Obesity and FDA Actions on Review of Weight Loss Drug Candidate, Lorcaserin

Dear Dr. Hamburg ,
We are writing to ask for your help with the FDAs review of Lorcaserin, a new drug candidate that helps patients with weight loss. There are serious questions that need to be answered regarding the FDAs review of what should be an important new tool for doctors in the fight to help their patients lose weight. You will not find many drugs on the market safer than this novel new compound. It should be approved.
For reasons unknown, the FDA officials reviewing the drug influenced a recent Advisory Committee to be biased against approval, using erroneous methodology and unscientific conclusions and innuendo. This negative bias was evident in the content of the FDA briefing documents, where the reviewers stressed that the drug met FDAs pre-specified efficacy goal by only a slim margin and went on to focus on claimed safety signals based on rat neoplasm findings. Those conclusions were false and misleading. The FDA briefing documents, presentations and lack of relevant expertise on the panel left members feeling spooked, uncertain, and unqualified to make a confident decision for approval.
Efficacy
Per the FDA, Lorcaserin meets the pre-specified guidelines for a weight loss drug with more than 35\% of patients losing at least 5\% of their body weight (47\% in this case) and approximately double the placebo (22\%), both arms having been also under a weight loss program with exercise and calorie intake reduction of 600 calories per day. The only adverse side effect reported significantly more in the treatment arm was a mild and transient headache. To one not well acquainted with obesity treatment, this benchmark may appear modest. It is not, and more pertinent, it meets one of the FDAs two, pre-defined alternative criteria. Importantly also, a large subgroup who took the drug experienced excellent efficacy. More than 22\% of the patients who took Lorcaserin (3X placebo,) lost more than 10\% of their body weight and the top quartile of responders lost 16\% of their body weight or an average of 35lbs. In addition, the treatment group improved their cardiovascular health including their blood pressure, heart rate, cholesterol, waste circumference, HbA1c, fasting glucose and quality of life. To put this into perspective, if 1,000,000 pre-diabetics were to take this drug, more than 220,000 of them would reduce their risk of becoming a full blown diabetic by more than 58\%, while improving their cardiovascular health. As one would expect, studies also show these benefits come with an improvement in their overall Quality of Life. Allowing Americans who have become obese and are at risk of becoming a Type II diabetic to take Lorcaserin would thus also prevent some additional disease instead of merely treating symptoms or reducing weight in the abstract. The impressive weight loss achieved by 22\% of patients and the 2/3rd of responders who achieved 5\% weight loss in the study is not modest. A drug that is safe, well tolerated and very effective for many of the patients would be a very powerful and much needed tool for physicians trying to improve their patients overall health and quality of life. Our country is facing a pandemic of obesity that cuts thousands of lives short every year and inflates our healthcare costs by millions of dollars. In my home state of Georgia, it is estimated that 1/3 of all deaths last year were attributed to obesity-related diseases. Physicians need safe and effective tools to help patients in their fight to lose weight and keep it off.
Neoplasms
FDA reviewers made a critical mistake in their analysis of mammary tumors in rats that changed the course of the Lorcaserin review. In the FDA Briefing Documents section entitled "Safety of Lorcaserin" in the 6th paragraph (Malignancies in Rats), the reviewer made a highly damaging, but incorrect, statement: "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."
This was absolutely wrong and misleading information. As explained by Dr. Gary Williams, a widely respected expert in toxicology and drug carcinogenics, it was based on unquestionably improper scientific methodology and assumptions. The statement implies that statistically, the 10mg /kg female dose (7x group) was significantly different from controls. However, the only malignant tumor detected in the 10mg/kg female was mammary adenocarcinoma, but it was not statistically significant from the control rats (Table 4, NS). Based on Table 4, breast tumors were statistically significant only if both tumor types (carcinoma and adenoma) are combined. While it is common to combine two types of tumors as long as the non-malignant type is known to progress to malignancy, that was not the situation here. This egregious error, improperly combining two distinct types of tumors in order to suggest statistical significance in the treatment arm, was then expressly suggested by the reviewer, both in the documents and at the meeting itself, to represent a possible safety signal. Several panel members, not being toxicologists or oncologists, and not having the benefit of having any FDA toxicologist or oncologist present to explain the underlying science, became concerned that if what the reviewer was representing were accurate, there might be a need for further study of that purported safety signal. As toxicology and oncology experts know, benign fibroadenomas are not a health threat to women. Had the FDA not made this error, the outcome of the panel vote would have been much different. If the reviewer truly did see this as a legitimate issue and didnt realize they had made a mistake, why did he not include at least one toxicology expert on the panel or at least have a toxicology expert available to testify before the panel to address the underlying science and to answer their questions? Without 1 or more toxicology experts on the panel, the committee was biased towards a no vote.
Earlier circumstances also cast doubt on the logic of the reviewer. The FDA knew about the rat data while Phase III trials in humans were on-going because the sponsor reported it as soon as it became known and well before the conclusion of the phase III trials. With that knowledge, the FDA advised the sponsor to continue with the human trials. If the FDA had had any legitimate concern that there could be any significant increase in cancer risk to humans because of this rat data, why werent the trials ordered stopped, and why were any new trials allowed to begin?
Dieticians, endocrinologists, cardiologists and statisticians (panelists) are not experts in toxicology, and they had no toxicologist expert on whom to rely, yet they were left to decide the fate of this drug. The only qualified expert to testify as to the risks of neoplasms in humans was provided by the drug sponsor, who made a compelling argument as to why there is in fact no risk at all to humans.
Dr. Gary Williams, an international authority on the subject of drug carcinogens, presented on Arenas behalf. Dr. Williams has written 500 papers on the subject and has participated in or chaired numerous government committees regarding drug carcinogens. There probably isnt a better qualified person in our country to review the risks Lorcaserin would pose to humans. His conclusion was that Lorcaserin does not pose a risk to humans at therapeutic doses and that there is a margin of safety of 17X the therapeutic dose. Dr. Williams disagreed with the FDA reviewers and their methodology underlying their conclusions (among other things, their having erroneously combined two distinct tumor types in rats). This evidence disproves the reviewers suggestion that the rat data suggests a cancer safety signal that could foretell an increased adenocarcinoma risk in humans taking Lorcaserin.
It is worth noting that a number of drugs that have shown similar results in rat neoplasm studies have been approved by the FDA, are widely used, and subsequently have not been shown to cause an increased cancer risk in humans. Other widely used compounds such as Aspartame have clinically shown increased risks of mammary neoplasms in rats at levels equal to a child consuming 2 cans of diet soda a day, yet it still continues to be the most widely used artificial sweetener in the country. The risk associated with the use of Lorcaserin in therapeutic doses should have been completely ruled out by the reviewers with a safety margin of 17X, just as Dr. Williams and his associates ruled it out. If the FDA reviewers were concerned enough to make this a focal point of the review, then the FDA reviewers should have included experts on toxicology and oncology on the panel.
To summarize:
FDA allowed human trials to continue knowing the results of the neoplasm testing on rats when reported by the sponsor.
Leading toxicology expert testified the reviewers conclusions were wrong and there is in fact no increased risk in humans at prescribed doses.
FDA failed to appoint any toxicology or oncology experts to the advisory panel or to present qualified experts at the hearing.
Lack of expertise on the panel led many panel members to vote No for approval.
No increased risk of neoplasm was shown in Phase III trials across thousands of patients.

The international expert on Drug Toxicicity, Dr. Williams, testified that:
Lorcaserin does not pose a risk to humans at the therapeutic dose.
All tumors of increased incidence (with the exception of mammary) were exclusive to male rats and at doses 56X times the therapeutic dose a human would receive.
Increased incidence of mammary tumors in rats was likely due to the rats age combined with the increased prolactin levels these developing rats were subjected to, at a critical point in the rats lifecycle when the mammary glands were still developing. This phenomenon was proven in a body of work that won the Nobel prize. Dopamine agonists cause similar prolactin increases as Lorcaserin did in pre-clinical studies. Prolactin increase is not a risk factor for cancer in humans. (Note: There were no increases in mammary tumors of mice, nor were there any increases in the trials involving over 7,500 patients.)
Dr. Williams agreed with the reviewer on many points, but he disagreed with the reviewer on the conclusion of the margin of safety for mammary tumors. The FDA erroneously combined two distinct separate types of tumors in their analysis instead of keeping them separate, and only that error supported the reviewers erroneous conclusion of statistical significance. Dr. Williams concluded that there is a 17X or greater safety margins for all tumor types including mammary tumors.

Valvulopathy
Valvulopathy was expected to be the core safety question discussed at the panel. The sponsor undertook the largest obesity trial ever for a weight loss drug and performed 20,000 echocardiograms to monitor for potential changes in patients heart valves. Not only was no increase in cases of valvulopathy found on patients taking Lorcaserin, but most of the patients who had valvulopathy at baseline, actually improved. As one of the expert statisticians on the panel stated during the committee meeting, the sponsor did about all they can do to rule out valvulopathy.
Long term use.
There was apparently concern about two year data reliability resulting from dropout rates. High dropout rates result from the fact that patients who perceive a lack of success with diet drugs tend to stop taking them. In the real-world, only patients who experience weight loss will continue to use the drug. This is one of the main reasons why drop out percentages tend to be so large in weight loss trials. Lorcaserin was no different; but importantly, 68\% of Lorcaserin recipients maintained their weight loss in Year 2 as opposed to only 50\% of placebo patients. If the FDA has concerns about the long-term use of Lorcaserin, a simple solution would be to approve it for use for up to only 1 year. That would facilitate collection of real-world data that could be used to consider whether to expand the label for longer term use in the future.
Before a rushed vote was cast at the conclusion of the Advisory Committee meeting, panel members expressed their confusion and uncertainty of the neoplasm data presented by the FDA, even though one of the worlds leading experts demonstrated why there was no risk to humans. When openly discussing the neoplasm question, a number of panel members expressed their frustration at not having experts available on the panel to further explain the neoplasm data. Dr. Henderson noted she had no problem with the efficacy, but neoplasm risk was her #1 concern especially because the FDA (erroneously) showed no safety margin. Dr. Gregg said he was spooked by this data and the FDAs conclusion that there was no safety margin and felt unqualified to make the judgment on neoplasm risk based on the animal studies. Dr. Gardner said he concurred completely with Dr. Greggs assessment. Dr. Proshan also agreed saying he felt lost at the explanation of the neoplasm data. During this line of discussion, Dr. Segal, unsure of the strength of the reviewers position, asked: Is it sometimes better to approve drugs even if you have to pull them later? A FDA representative responded with an intimidating comment to the effect that if you approve it and it turns out to cause cancer, your name will always be associated with having approved a drug that caused cancer.
In the face of uncertainty around misrepresented cancer risk and the FDA urging the balancing of slim efficacy with associated risks, it is a wonder that even 5 of the panelists voted to approve the drug. The 9 who voted not to approve Lorcaserin based on the current set of data all stated that it was a promising compound but there were too many uncertainties around neoplasms and they were concerned about long term use given these unknowns.
The pendulum has swung too far at the FDA if they influence Advisory Committees to vote no for a drug that poses very little risk to the public at large, and certainly less than currently available therapies, and where there is a demonstrable clinical benefit in terms of additional weight loss and reduction in cardiovascular risk factors. This is particularly true if the methodology underlying that influence is unscientific and based upon assumptions that are contrary to accepted scientific knowledge.
Obviously, the deficiencies found and reported in November 2007 regarding large gaps in scientific structure, staffing and capability at the FDA persist. See FDA Science and Mission at Risk , report of the Subcommittee on Science and Technology. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA\%20Report\%20on\%20Science\%20and\%20Technology.pdf
As that report noted, the nation is at risk if FDA science is at risk. The deficient science used by the reviewer in this case and the absence of appropriate scientific expertise at the hearing resulted in a panel vote that did not support approval of Lorcaserin. That result puts America at risk. I ask you to intervene and to prevent that risk from becoming manifest.
At a minimum, the FDA should approve Lorcaserin for weight management with a label for people who would have qualified for the sponsors Phase III trials. If there is a concern about long term use (there should not be), the FDA should limit the use for up to 1 year, facilitating the collection of additional data. That 1 year could mean the difference of hundreds of thousands of Americans losing 10\% or more of their body weight, significantly improving their health and quality of life, while subjecting them to very few side effects and risks.
To deny Lorcaserin based on erroneous assumptions and a panel vote where the needed expertise was lacking would be unconscionable. Lorcaserin unarguably met the FDAs own pre-specified criterion for efficacy. The data submitted also show statistically significant reduction in important cardiovascular risk factors. It is safe. Its use would reduce the nations health care bill by many millions, perhaps billions of dollars. It is for these reasons that the group of physicians that treats obesity patients, the American Society of Bariatric Physicians, supported approval of this drug.
Please do the right thing for patients and approve Lorcaserin. Good science supports it. Intellectual honesty and good government demand it.
Sincerely,
Concerned Citizen

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