On February 22, 2012, the Endocrinologic and Metabolic Drugs Advisory Committee will meet to discuss new drug application (NDA) 22-580 for QNEXA (phentermine/topiramate), submitted by VIVUS (VVUS). Here, we update our original panel vote prediction to reflect new information contained in the FDA briefing documents released last Friday.
Voter names (draft meeting roster), current prediction, previous prediction, votes from past obesity drug panels, area of expertise, and links to bios are listed in the google spreadsheet below.
- Blue – Will serve on the panel
- Yellow – Will *not* serve on the panel
- Green – Current sitting member of EMDAC
- Red – Originally predicted not to serve on panel
- Orange – New addition not considered in our original analysis
- Gray – Highlights members who voted on two or more previous panels
Highlights from Previous Prediction
- We correctly projected 22 potential panel members.
- Burman, Flegal, Goldfine and Henderson were asked to return. We originally predicted they would not serve on this panel due to their EMDAC terms expiring.
- FDA included seven fresh non-EMDAC members who have not served on any of the obesity drug panels. Their names are highlighted in orange.
- There is minimal cardiovascular representation on this panel. FDA decided to include more teratogenicity experts, including Suzanne Gilboa who is attending as a non-voting speaker. More on her below.
- One of the caveats of our previous prediction was that Flack, Hiatt, Segal, Balish, and Hirsch were the members least likely to be asked to serve on this panel. That turned out to be the case, as none of them are included on the draft roster. Consequently, this panel lost a lot of projected yes votes from our previous prediction. Lost votes are Yes 8, No 3.
Based on the projected votes from the previous prediction, the tally currently stands at Yes 5, No 6. We need to predict the votes of 11 new members not included in our previous analysis. Let’s get started.
How will each person vote?
Erica Brittain – No
Brittain did not serve on any of the previous obesity drug panels. We project a no vote based on her comments at the dapagliflozin panel. She said, “So like I said, I really am on the fence about the issue of whether you approve now versus later, when there’s more information. What I think is most important is to get more information. And even in the course of the randomized study, that could be monitored as it’s ongoing. And if the news looks good early on, perhaps that could be used to change — depending on what decision is made now, or vice versa. So it wouldn’t necessarily have to wait for eight years or however long it would take to do the study.”
If her thought process transfers to a CV outcome study, then she will advocate for QNEXA following the same path as CONTRAVE.
Kenneth Burman – No
At the last QNEXA panel, Burman said, “On the other hand, the medication has serious potential adverse effects, including potential teratogenicity, increased suicidal ideation, cognitive issues, decreased bicarb, tachycardia, and possible renal stones. Some of these side effects are serious and could be life-threatening, and they have to be weighed against the potential of a relatively modest weight loss and its long-term health benefits. It is difficult if not impossible to weigh these issues since the clinical studies are only for about a year and these medications, if approved, will be used for a much longer time frame in a much wider population. And it is difficult to extrapolate the potential adverse effects to this larger population.” He was on the fence, concluding his remarks, “However, I could have voted yes, and will feel more assuaged if a lot of these issues and restrictions were addressed, especially with regard to warnings for specific populations, as mentioned.”
The updated CV data may not assuage Burman’s concerns. First, the statistical review and evaluation of Study 305 states “we consider the strength of the data in Study 305 to be equivalent to that of an observational finding.” Study 305 is an enriched subset of the best responding sites from study 303. These results will not help Burman extrapolate how QNEXA will work in the broader population.
Likewise, the teratogenicity signal in the FORTRESS data will not assuage his concerns. The FDA says “a restrictive REMS is not practicable give the serious indications for topiramate use and the FDAAA requirement to refrain from creating undue burden on access for patients with serious illnessses.” VVUS is handcuffed in making the REMS restrictive enough to satisfy Burman in this case.
David Capuzzi – No
Capuzzi voted no on the last QNEXA panel. His main concern was prescribing phentermine to patients with a history of cardiovascular disease. He mistakenly voted yes before changing his vote to no, attributing his mistake to panel inexperience. He thought the panel’s concerns summarized by Burman would be addressed prior to approval.
The FDA briefing docs say “It is unknown what the clinical significance of PHEN/TPM’s cardiovascular effects and metabolic effects will be in a higher-risk cardiovascular population with chronic treatment.” We therefore feel Capuzzi will continue to vote no.
Robert Clancy – No
Clancy’s expertise involves Topiramate for White Matter Neuroprotection During Newborn Heart Surgery to repair congenital heart defects. As a pediatric neurologist who helps newborns with heart defects, we think he will be wary of approving a drug that can increase birth defects.
Clancy also published an article entitled Perspectives of epilepsy care in the United States: Children and the developmentally disabled which says, “US physicians may be held legally responsible for the occurrence of birth defects in offspring of mothers who have taken AEDs during their pregnancies.” The size of the obese population has enormous consequences for physician liability and he may feel the benefits of QNEXA do not outweigh the risks, not just for patients, but for doctors as well.
Melanie Coffin – Yes
Coffin voted yes for all three obesity drugs. She will continue to vote yes as the patient rep.
Janet Cragan – No
Cragan is a medical officer in the Birth Defects Branch at CDC. At the last QNEXA panel she said, “But I think for a woman who has a seizure disorder that topiramate’s the drug that really will control her seizures, the benefits probably outweigh the risks that might be out there. But I’m not so comfortable saying that’s the case for a drug that’s likely to be marketed for a very common exposure, where there are a lot of reproductive-age women who will be likely to take it, and probably a large number of inadvertent pregnancy exposures, I think.”
She went on to say in her remarks explaining her no vote, “But in the end, I couldn’t really justify widespread use with the reproductive outcomes concerns that we have. And as I listened to the panel members discuss the other adverse events, it actually raised my level of concern rather than lessening it. I think the situation where the only way we’re going to resolve the reproductive risks, if we can, is to have a large number of women take the drugs and see what happens, is the situation we’re in with human teratogenicity, often. And that’s really difficult, but that’s just the nature of the situation.”
The teratogenecity signal is real. Although topiramate’s risk/benefit profile is favorable for seizures, Cragan is not comfortable with this risk/benefit profile in the broader obese population. We feel Cragan will continue to vote no.
Eric Felner – Yes
Felner served on the LORQUESS and CONTRAVE panels, voting no both times. His statements indicate he is concerned more about the magnitude of efficacy and long-term nature of the efficacy than with the general safety issues. Although Felner voted no for LORQUESS and CONTRAVE, we believe he will vote yes for QNEXA because it is the most efficacious of the three drugs and weight loss is sustained through the two year SEQUEL data.
Here are his comments from the LORQUESS panel: “But I think when it comes down to it, I really didn’t have a lot of issues with the risk. But obviously some other people here did, and it made me look at it a little more closely. And then it made me look back at the real benefit at least today of this drug. And I just didn’t see it as being that efficacious for even the group that was studied. And what bothered me I think a little more about it was looking at the second year of the data. When they didn’t maintain weight as we’ve seen in some 10 other drugs, they actually gained the weight back right after the year. And if they would’ve continued past two years, it may have been even right back up to baseline even on the drug. … But that was the real key for me, was that I had a lot of trouble really seeing the benefit at least today.”
Here are his comments from the CONTRAVE panel: “This is similar to what I have said at least at a previous meeting, that I’m not overly concerned about the events or the risks that we see today at one year of studies. I think more time would, obviously, help that. But I’m actually more concerned about the efficacy. I don’t think there’s a tremendous amount of weight loss when you really look at this in all four of their studies, especially if you throw out the one study that involves the lifestyle or the behavior modification, which I think we call safely agree that very few people actually do that in real world. But I am actually not that disappointed in the overall vote, even though I voted against it, because I think of all of the drugs that we’ve looked at, this definitely had the lowest signal from an adverse event and had very similar efficacy. But I think another year of information would be very helpful to see if the weight either goes down even further or at least does not increase.”
Katherine Flegal – No
On the past QNEXA panel, Flegal said, “I think my views — I think it was both colored, maybe, by our experience with Avandia and the safety concerns that we should deal with them before rather than afterwards. As Lynn McAfee said, this is like a public health experiment, a large gamble. And I think widespread usage even in inappropriate populations is difficult to prevent. We have one-year information, but this drug will likely be used for a long time. It really addresses surrogate endpoints, and there’s minimal information on subgroups, even, like sex and ethnic groups. I think we need more data. I would like to see more data on body composition because there’s — I’m thinking about the health effects have more to do with body composition aspects than simply BMI alone.”
She repeated these sentiments on the LORQUESS panel, saying “But I think there are just these unanswered concerns about the risks that really need to be dealt with, and also that we need to see something about how this would benefit in a population that stands to benefit more from it.”
Flegal will not vote for approval until the risks have been thoroughly vetted in a large trial that can track CV and teratogenicity.
Allison Goldfine – Yes
On the last QNEXA panel, Goldfine said, “Of all the things that concerned me most was the pregnancy issue, and that to me was very problematic because I don’t want a real world trial where the vulnerable are not the ones who agreed to the risk exposure that was enforced upon them. And yet I also clearly agreed that you would not be able to get this data from a clinical trial design, and I think that’s what finally swayed me. Therefore, the risk management program and the registries and the careful assessment that these are established before the approval, and that the mechanisms are in place, are going to be essential to support the vote that I was on the fence because of all of these lists of restrictions, and in addition some of the others that had been discussed, including Holter monitoring, bone mineral density, and others that were not as major as the pregnancy and depression.”
At the LORQUESS panel, Goldfine said, “I voted yes. And once again I’ll say I found this a very very hard decision to make. As I’ve said before at many of these. I think that it had very very small magnitude weight loss relatively, but I think that that can be clinically quite important. And I think that all of the surrogate endpoints in this particular drug looked like they were moving in the correct direction. And I think that that was important to me.”
At the CONTRAVE panel, Goldfine said, “I think that the more effective it is, the more risk we would tolerate. And I think that partly we have this uncertainty with the magnitude of potential risk and the magnitude of benefit that we’re seeing. I am struck by the epidemic of obesity and the requirement; that physician providers, health care providers, have to have something additional in their armamentarium. And when there’s nothing there, then I have a greater threshold for accepting a potential risk. I think that I am somewhat reassured that a lot of people actually stop the therapy if they are having lack of benefit. And so in the clinical arena, that would actually mitigate some of the risks, and following blood pressure and pulse and weight for continued therapy would be very beneficial. And I don’t need a drug that’s actually going to be beneficial to everyone to have it be useful in a sub-population of responders. … Finally, I want to say that I’m not sure — that although people have talked about it, if we’re not saving cardiovascular morbidity and mortality — that there isn’t a benefit to the weight loss. I think that the company might want to characterize more benefits to arthritis and GERD and other things that can be very important to quality of life, measures that may mitigate some relative risk in the other categories as they go forward.”
Despite her qualifying remarks, Goldfine voted yes for all three drugs. We feel she will continue to vote yes.
Edward Gregg – No
At the LORQUESS panel he said, “I felt the weight loss, though not great, was acceptable. I felt the profile of risk factor benefits was encouraging, actually. And there wasn’t any clear evidence actually that this was a dangerous drug. That said, there was enough doubt raised about some of the risks, lack of understanding in some of the mechanisms underlying those risks that forced me to take a harder look at what I saw as the crux of the benefit, which would be on the magnitude of the risk factors, not necessarily the spectrum but the magnitude of the risk factor benefits after you think about and take into account loss to followup and so on. And when I did it that way the risk to benefit just didn’t quite pass that bar, so on balance I think the drug is promising but it’s not quite there yet in terms of showing the evidence.
QNEXA is more effective than LORQUESS, but it has a different risk profile regarding CV outcomes and teratogenicity. We feel he will waver on the teratogenicity data. That will raise a doubt in his mind, similar to LORQUESS, which will prevent him from voting in favor of the drug.
Jessica Henderson – Yes
At the last QNEXA panel, Henderson said, “I voted yes for approval. I did vacillate between yes and no because of the lack of long-term safety data and also the real world applications that we all discuss we’re worried about. But I voted yes because, number one, the sponsor did satisfy the criteria for the weight loss benchmarks. But mostly what made me vote yes is the quality of life survey data. Five out of the eight quality of life measurements were statistically significant in improvement. As the consumer representative, I put a lot of credence into quality of life and the pursuit of life, liberty, and happiness, and a patient’s right to do that. So the quality of life data actually put me in the yes category.
At the LORQUESS panel, Henderson said, “I voted no. I agree with all the comments that this is a promising drug, and I would encourage the sponsor to reapply. I love the quality of life data, that’s one of my complaints when there’s not the patient perspective there, and that was there. But I voted no because there’s too much uncertainty. Too much uncertainty about the brain and breast tumor development, and too much uncertainty of the real life population that this would be used in. So again, I do think it’s promising, but just too much uncertainty at this time.”
The two-year data was consistent with the one-year data. We feel that will be enough to satisfy Henderson and she will continue to vote yes.
Sanjay Kaul – Yes
On the last QNEXA panel Kaul said, “I voted yes. There’s a very fine line between a yes and a no vote, and thankfully, the FDA pays more attention to the discussion rather than just counting the beans. My yes vote comes with a lot of conditions. And I will not hold it against the sponsor if they interpret my yes vote as a no vote. First of all, it should only be approved for low to medium dose, not for the high dose, because all the safety signals appear to cluster in the high dose. The sponsor should be required to conduct a pharmacodynamic study in the short term addressing the concerns that were expressed earlier on during the discussion, focusing specifically on commonly used medications, including cardiovascular and over-the-counter medications. There should be a clinical outcome study designed to rule out cardiovascular risk. It should be implemented within three to six months. The protocol should be with the FDA within three months. And the study outcomes should be available to the FDA for assessment within three to five years. It should be a conditional approval. If they don’t meet these 2 conditions, the FDA should have the right to withdraw the approval. There is already a FADAA program that sort of enforces postmarketing requirement for assessing safety signals. I have no doubts about its effectiveness. But I think it concentrates the sponsor’s mind if we impose, moving forward, a preapproval requirement to evaluate cardiovascular risk. And I think the FDA should seriously consider that as an option. It’s already been mentioned what patients it should not be given to. There should be strict contraindications in patients with arrhythmic heart disease, severe ischemic heart disease, patients with hypertensive heart disease, including TI and stroke, and it should be contraindicated. And there should be a prominent warning mentioned for adverse effects, particularly the drug interactions that have already 1been elucidated. So as I said, a very fine line between a yes and a no vote.
On the LORQUESS panel he said, “I really didn‟t think that the current portfolio of evidence was sufficient enough to persuade me that a desirable benefit risk had been demonstrated.”
On the CONTRAVE panel he said, “In my opinion, the drug does not yield the weight loss efficacy margin that allows an acceptable safety trade-off consideration, especially given the adverse blood pressure and heart rate signals.” And regarding a pre (A) or post-approval study (B), “I voted A. However, I could have been persuaded to vote for B if the weight loss efficacy had been more impressive.”
It seems Kaul favors QNEXA’s efficacy to LORQUESS or CONTRAVE’s. We think he will stick with his yes vote and append the same conditions, which as he said, could be interepreted as a no vote.
Michael Lauer – No
Lauer is an expert in heart rate as a predictor of cardiovascular health, specifically, heart rate recovery. In multiple articles (here and here) he states there is an inverse association between resting heart rate and life expectancy. In the first link, he says “There is an extensive epidemiological literature linking heart rate to mortality in large human populations. As heart rate increases to 75 to 80 beats per minute, there are marked increases in total mortality and mortality due to coronary heart disease.”
In table 58 PHEN/TPM pushes the average heart rate just to the edge of the danger zone of 75 bpm. In table 62, a higher percentage of patients on PHEN/TPM experience heart rate elevations in the danger zone compared to placebo. The regression to the mean of BPM means people are regressing back to the danger zone. They are not improving enough to get out of it.
The rate pulse product improvement could be considered a positive, as Lauer has stated RPP is a sign of increased physical fitness. But the observed RPP decrease is a result of blood pressure declining more than the pulse increased. Also, the average baseline blood pressure in Table 62 of 130/80 is in the normal range. The average subject is not hypertensive; therefore it’s unclear what the benefit of lowering blood pressure and RPP will be if the pulse increases.
Study OB-204 probably is not conclusive in showing the benefit of a dip in nocturnal heart rate.
In summary, we feel Lauer’s experience with heart rate will cause him to vote against approval.
Elaine Morrato – No.
At the QNEXA panel Morrato said, “I was just doing some back-of-the-envelope calculations. If we take some conservative market estimate as to how many women are going to be exposed to this, in the materials that they share there’s about 9 million bariatric surgery patients a year. There’s about 6 million on phentermine. If we just assume out of that, which is really the high risk population, that this is being claimed to want to market against, let’s assume one million women. And let’s assume that we are not able to, in the real world, achieve any better or worse than what they saw in their clinical trials, which was about a 1 percent pregnancy rate, if I understand right. You know, we’re looking at 10,000 pregnancies in just this select population that we’re feeling that the benefit and risk makes sense. If the drug is really used as broadly as we think it might be, then you have a much larger exposure in numbers of pregnancies. And as one said, I think in the open hearing, no one wants to conduct a large public health experiment on the population. I think we need to have a better sense of really what the risk is or constrain the use of the product so it’s really among those patients where we know the benefit really does outweigh the risk.
We feel the teratogenicity signal will cause Morrato to continue to vote no.
Sonja Rasmussen – No
The draft roster includes a non-voting speaker, Suzanne Gilboa, from the National Center on Birth Defects and Developmental Disabilities, CDC. Gilboa and Rasmussen co-authored a paper entitled, Association between prepregnancy body mass index and congenital heart defects.
Rasmussen touched on QNEXA and adverse infant outcomes associated with obesity in a presentation last year. One possible line of thought regarding these findings is that QNEXA lowers pre-pregnancy BMI, lowering the risk of congenital heart defects, offsetting the increased risk of oral cleft. However, we don’t think that’s how Rasmussen will view the data.
For a preview of Gilboa’s topiramate talk, see this presentation. The very last bullet point says, “If pooled results represent “truth”, the risk of CL/P would increase from around 0.7 per 1,000 births to 2.5 per 1,000 births (compared to baseline risk of 20-30/1,000 for any major malformation).” That’s about a 3.5x increase in oral cleft.
Gilboa also co-authored this paper, Influencing clinical practice regarding the use of antiepileptic medications during pregnancy: Modeling the potential impact on the prevalences of spina bifida and cleft palate in the United States. Valproate, another AED, has a 5.8x increased risk of oral cleft and is *not* prescribed to epileptic women who want to become pregnant.
BMI is weight/(height^2). Table 3 shows the mean BMI of subjects at baseline was over 35. QNEXA’s 10% weight loss leaves the subjects with a BMI over 30, still at high risk for adverse infant outcomes associated with obesity. QNEXA’s weight loss is not substantial enough to reduce the risk of congenital heart defects when compared to the increased risk of oral cleft. Additionally, QNEXA will be used off-label by non-obese women looking to lose a few pounds – these women will only experience an increased risk of oral cleft without any decrease in congenital heart defects.
Gilboa, Rasmussen and Cragan are all colleagues studying birth defects at CDC. We feel Rasmussen will vote no for the same reasons as Cragan.
Michael Rogawski – Yes
At the QNEXA panel, Rogawski said, “Yes. I just wanted to state what may be obvious, but maybe not. And that is that these teratogenicity studies are extremely difficult to do. They take a long period of time, and there’s no way that they can be done premarketing. They have to be done in a postmarketing fashion when large numbers of women are exposed. So I just wanted to emphasize that fact, that this wouldn’t necessarily be a reason not to approve the drug.”
“So I think that in terms of balancing the risks and the benefits here, I came to my conclusion to vote in favor of approval because it’s clear that these two components, as well as the combination, are indeed going to be used by patients because they are available. It seems to me that the best use by patients would occur with the most information and with the proper labeling, the proper education, and so forth, as would be done if the sponsor was marketing the drug and presenting the drug combination to the public. So I think, overall, there’s a greater concern with respect to public safety if we have non-approval because that means that we don’t have the benefit of the additional information and education, risk mitigation strategies, and so forth, being presented to the public. So that’s the reason why I voted in favor of approval.”
We don’t believe the FORTRESS results will sway Rogawski into changing his vote, since he believes teratogenicity data can really only be studied in a large-scale post-marketing study. We think he will stick with his previous yes vote.
Robert Smith – Yes
Smith is an expert in diabetes research. On the zetia/vytorin panel he specifically asked questions about diabetic study subjects. We expect Smith will again focus on diabetic outcomes.
From the FDA briefing docs, “In a subset of overweight or obese subjects with type 2 diabetes at baseline, high-dose PHEN/TPM treatment reduced HbA1c by 0.3% compared to placebo treatment in study OB-303. Mid and high-dose PHEN/TPM treatment reduced HbA1c by 0.4% to 0.2% compared to placebo treatment in a subgroup of subjects with type 2 diabetes in study OB-305.” This is right at the clinically meaningful level as outlined in the FDA Guidance for Obesity Drugs. QNEXA also had lower incidence of new onset diabetes.
In a paper Smith co-authored, Obesity and Type 2 Diabetes: What Can Be Unified and What Needs to Be Individualized?, the discussion states, “Finally, safe and effective centrally acting drugs that decrease appetite or increase satiety are urgently needed. However, as regulatory agencies increase the need for safety testing, fewer new and innovative approaches for weight loss are being developed because of the prolonged time and immense expense involved.”
QNEXA seemed to improve diabetic outcomes. We think Smith’s focus on diabetes and the desire for new drugs will cause him to vote in favor of approval.
Myrlene Staten – Yes
Staten is a challenge to predict because she has never served on an advisory panel before. Her research output seems to be centered around childhood diabetes and bariatric surgery. She wrote a book chapter on Pharmacologic Therapy for Obesity, but the book was published in in 1994 (it still advocates the use of fenfluramine!).
In her book chapter, she outlines four characteristics for an ideal drug.
- No potential for abuse or dependence
- Produces loss of body fat without significant loss of lean body mass
- Maintains or continues weight loss during chronic administration.
- Can be taken safely with chronic administration
The fourth point is the key point. Will she view it as safe? As a diabetes expert, we think she will have an opinon similar to Smith and vote for approval.
Abraham Thomas – Yes
Thomas was voted conservatively on the first QNEXA panel, raising all of the safety issues in his summary. He became more liberal in the LORQUESS and CONTRAVE votes, despite stating there was marginal efficacy for both drugs. In Thomas’ case, we feel QNEXA had the misfortune of being the first of the obesity drugs to face a panel. Had it come later, he would have voted in favor. Thus, we think he will change his vote on QNEXA to positive to maintain consistency with the LORQUESS and CONTRAVE votes.
Lamont Weide – No
At the QNEXA panel Weide said, “If, with a year’s trial, you have double the depression risk and you have some cardiovascular questions, I would like to see it extended. I would like to see the at-risk population be sicker, if you will, so that we can find out whether or not these safety concerns are going to be a major issue. I would agree, I am really sick of taking medicines off of the market after they’ve been on a year or two because we’ve identified something that we didn’t know about. And that really is some of what has given the FDA a reputation outside in the public.”
At the CONTRAVE panel Weide said, “I just pray and wish someday that we will have something that gives us 10 percent weight loss, that gives us long-term results for our patients, because let’s face it, obesity is a long-term problem. It is not a short-term problem. That means that when we’re looking at all these drugs, these agents that are coming before us, the question is going to be, if these patients aren’t taking it short-term anymore and they’re taking it long-term, what is our responsibility to protect them from the long-term implications of taking these medications and what are the risks?”
Weide will get his wish regarding a 10% weight loss with QNEXA. But he has consistently voted against the weight loss drugs because he is concerned about long-term safety. Study 305 does not satisfy his desire to see how QNEXA performs in a “sicker” population. We believe he will also latch onto the teratogenicity data and vote no as a result.
Almut Winterstein – No
Winterstein is a sitting member of the Drug Safety and Risk Management Advisory Committee. She has had serious concerns about elevated heart rate caused by ADHD drugs in children (see articles here and here).
As a member of DSRMAC, we think she will be especially wary of the increased heart rate *and* the teratogenicity, causing her to vote no.
Susan Yanovski – Yes
Yanovski has written a number of obesity editorials in NEJM. She says in her 2005 editorial, “An improved armamentarium of therapeutic approaches is needed to promote and sustain weight loss safely and effectively in obese patients and to prevent or ameliorate many obesity-related conditions. Advances in our understanding of the complex systems regulating energy balance, the genetic determinants of obesity, and the environmental factors that promote obesity should lead to the development of more effective and targeted treatments in the future. Ultimately, our goal must be to use this understanding to develop more effective strategies not only for treatment, but also for the primary prevention of obesity.”
Obesity Action, wrote a letter to CDER director Janet Woodcock, suggesting Yanovski as a potential expert to consider for future obesity drug adcoms. If Obesity Action is lobbying for Yanovski’s inclusion then they must feel Yanovski is sympathetic to their cause of expanding weight loss treatment options. Although Yanovski may have some reservations about safety, we feel she will vote yes.
Where does this leave us?
Our updated tally is Yes 10 No 12. This is a very close vote and one or two votes could swing it in either direction. But the margin has swung towards a no vote compared with our previous prediction due to the exclusion of members who we predicted would mostly vote yes.
FDA is clearly going to stress the teratogenicity issue. They are bringing in Suzanne Gilbao as a non-voting speaker. They added Sonja Rasmussen and Almut Winterstein to the panel. VVUS is stuck between a rock and a hard place when it comes to REMS because they can’t make it restrictive enough to overcome safety concerns.
On the flip side, cardiovascular expertise is underrepresented on this panel. We believe this is a result of the upcoming 3/28-3/29 EMDAC where the committee will discuss the role of cardiovascular assessment in the preapproval and postapproval settings for drugs and biologics developed for the treatment of obesity. Question 4 about a pre or post approval study is a discussion question, rather than a voting question like it was during the CONTRAVE panel. Whereas the pre or post approval question dictated the risk/benefit question for CONTRAVE, the question of approval is now separated for QNEXA. FDA has punted the question of a pre or post approval outcome study to the upcoming EMDAC.
We conducted our traditional behavioral analysis of the voters listed on the draft committee roster to provide insight into how this panel might vote based on their overall past voting records. For more information on how we analyze voting behavior, please read our adcom behavioral analysis.
Of the 22 voting members listed on the draft roster, 15 members have served on 1 or more committees in which the vote was non-unanimous. Non-unanimous votes provide the differential voting patterns that allow us to analyze voter behavior.
The average liberal-conservative index for this subgroup is 0.1295. We expect a close panel vote with a margin closer than 70/30, so based on our logistic regression of past panels with closer than 70/30 splits, we estimate a 49.6% chance that this panel will vote for approval.
IMPORTANT: This behavioral analysis is secondary to a scientific analysis. A thorough analysis of safety and efficacy should form the cornerstone of any due diligence, as safety and efficacy are the primary concern of the FDA. Please consider this behavioral data as a supplemental factor if the outcome remains unclear after evaluating the safety and efficacy.
It’s going to be a very close vote, but both our detailed biographical analysis and our traditional behavioral analysis point to a small majority voting against approval.
For an explanation of the table headers, please see the “individual results” section of the methods page. Please click each name for a detailed voting history.
|Name||Num Votes||Proportion Yes||Proportion No||Proportion Abstain||Num Informative Votes||Num Inverse Yes||Inverse Yes||Num Inverse No||Inverse No||Liberal-Conservative Index||Maverick-Conformist Index|