Michael Murphy CFA
New World Investor
3960 Broadway, Suite 103-168
Boulder, Colorado 80304
NewWorldInvestor@gmail.com
October 5, 2010
Secretary Kathleen Sebelius
Department of Health and Human Services
200 Independence Avenue S.W.
Washington, D.C., 20201
Dear Madam Secretary:
For reasons unknown, the FDA officials reviewing lorcaserin, a new drug to treat obesity, 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 FDA’s 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.
On September 16, 2010, an Advisory Committee of the Food & Drug Administration was misled by this erroneous analysis of the data for lorcaserin, a new chemical entity designed to safely help obese people lose weight, especially those in danger of progressing to diabetes. Due to an erroneous analysis of benign tumors in rats at extremely high dosages, the Advisory Committee voted 9-5 against recommending lorcaserin for approval. It is clear from the transcript of the hearing that had the analysis been correct and complete, and had the Advisory Committee included professionals qualified to understand the data, the vote would have been overwhelmingly for approval. 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 invited a toxicology or a carcinogenic expert to be on the Advisory Committee as support for any concerns the panelists might have had regarding the relevance of rat tumors 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.
The full FDA is now considering lorcaserin for approval, with a PDUFA date of October 22, 2010. The action of the Advisory Committee normally weighs heavily on the decision. I believe the FDA should postpone the PDUFA date and convene another Advisory Committee with qualified experts to specifically address the data that was erroneously analyzed. I am writing to ask you to lend the power of your office to be sure lorcaserin is given an unbiased review by qualified experts. Lorcaserin is 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.
I want to first summarize the analysis the FDA made, and then explain why it is wrong in light of industry standards and directly refute their analysis with scientific evidence. I will then conclude with the implications of approving lorcaserin or not, which will have a dramatic impact on the Medicare budget to treat several diseases. It is my hope that you can intervene to see that another Advisory Committee is convened.
You should understand that the long-term effects of this event could result in irreparable damage to the biotechnology 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 against Arena Pharmaceuticals. These data clearly were adjusted by the FDA to show significance in cancer occurrence where none existed. Toxicity and carcinogenicity studies are designed specifically to find the very high levels of a drug at which these toxic events occur. However, these studies are not designed to explain or necessarily discover the mechanism for tumor growth, and finding tumors in rats at very high levels of a drug does not have any implications for human use at normal dosages.
The data show that Lorcaserin is a safe and efficacious drug. There is no other single new chemical entity near approval that could bring down our national health care costs as dramatically as lorcaserin. 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://tinyurl.com/3aj9nyg.
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 FDA’s 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 in 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 patient’s 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. It is estimated that 33% 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.
Summary of the FDA Analysis on 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 sixth 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 (twice a day).”
This was absolutely wrong and misleading information. As explained by Dr. Gary Williams, a widely respected expert in toxicology and drug carcinogenics who testified at the hearing, 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 (carcinomas and non-cancerous adenomas) are combined. While it is reasonable to combine two types of tumors if 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 (inexplicably) not having the benefit of having any FDA toxicologist or oncologist on the panel or at least 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 (fibroid tumors) 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 didn’t 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 one 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 weren’t 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 Arena’s behalf. Dr. Williams has written 500 papers on the subject and has participated in or chaired numerous government committees regarding drug carcinogens. There probably isn’t 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 reviewer’s 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 ½ 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 reviewer’s 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 rat’s 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 or monkeys, 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 reviewer’s 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 patient’s 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 one 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.
The Panel Vote
Before the votes were cast at the conclusion of the Advisory Committee meeting, panel members expressed their confusion and uncertainty regarding the neoplasm data presented by the FDA, even though one of the world’s 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 FDA’s 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. Gregg’s 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 reviewer’s 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 the 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.
This Drug Approval Process Has Gone Off The Rails
The pendulum has swung too far at the FDA if they provide erroneous analyses, 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 substantial 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 the pdf FDA Science and Mission at Risk , report of the Subcommittee on Science and Technology, at http://tinyurl.com/36ordua.
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 sponsor’s 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 one year, facilitating the collection of additional data. That one 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 analysis and a panel vote where the needed expertise was lacking would be unconscionable. Lorcaserin unarguably met the FDA’s 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 nation’s health care bill by 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 use the power of your office to support the approval of lorcaserin. Good science supports it. Intellectual honesty and good government demand it.
Very truly yours,
cc: The White House
First Lady Michelle Obama
1600 Pennsylvania Avenue NW
Washington, DC 20500
Sen. Charles Grassley
135 Hart Senate Office Building
Washington, DC 20510
Sen. Joseph Lieberman
706 Hart Office Building
Washington, DC 20510
Joshua Sharfstein
Principal Deputy Commissioner – FDA
10903 New Hampshire Avenue
WO1 – Room 220
Silver Spring MD 20993
Mary Parks
CDER Division of Metabolism and Endocrinology Products – FDA
10903 New Hampshire Avenue
WO22 – Room 3362
Silver Spring MD 20993
Janet Woodcock
CDER Director – FDA
10903 New Hampshire Avenue
WO51 – Room 6133
Silver Spring MD 20993
Curtis Rosebraugh
CDER Office of Drug Evaluation – FDA
10903 New Hampshire Avenue
WO22 – Room 3214
Silver Spring MD 20993
John Jenkins
CDER Director of New Drugs – FDA
10903 New Hampshire Avenue
WO22 – Room 6304
Silver Spring MD 20993
