Posts tagged ‘PDUFA Date’

QSYMIA Approved

The FDA approved QSYMIA, the Vivus compound for the treatment of obesity.  As regular readers of this site will know, I have been opining for many months that I didn’t think this would happen soon, if at all.

There has never been a doubt in anyone’s mind that QSYMIA (nee QNEXA) was the most effective of the diet drugs that have been submitted to the FDA.  The issue has always been safety.  For some it was the cardiovascular risk particularly in light of the recent negative experience with fen-phen.  For others, it was the potential for neurological problems.  While a concern, I never felt these potential problems would be the obstacle to approval.  For me, it was the fact that this was an acknowledged teratogen and a large part of the population of patients who would use this drug would be women of child bearing potential.

The basis for my concern goes back to the very foundation of the modern FDA concern for safety.  The Food and Drug Amendments of 1962 were a response to the thalidomide tragedy in Europe.  The US was spared because the drug was not approved here.  The 1962 Amendments were enacted to prevent such a tragedy from happening here.  Some have said that since that time, the FDA has overemphasized safety, often criticized for keeping life saving drugs off the market because of a potential for harm.  With the approval of QSYMIA, those critics are silenced – for now.

BELVIQ (lorcaserin) Approved

My webmaster tells me that we have had a record number of visitors to our website this week. Thank you all for visiting us. I suspect many of you were looking for some last minute comments before the June 27, 2011 PDUFA Date for lorcaserin. I didn’t post anything because I had nothing new to add. As I had said in the past, I thought Arena (ARNA) had a better chance of getting approval for LORQESS than did Qnexa because the cardiac problems could be monitored and managed while the teratogenicity issue with Qnexa was binary, ie, all or nothing on the teratogenic effect.

Well, Arena is rejoicing and ringing the BELVIQ! (nee LORQESS). The folks at Vivus (VVUS) and probably some of the analysts are seeing the BELVIQ approval as a sure sign that an approval for QNEXA is just around the corner. I say not so fast. If you remember, a major concern expressed here and raised by some at the Advisory Committee meeting was whether women of child bearing potential who were overweight would heed the warning to avoid getting pregnant, especially in light of the number of women in the QNEXA controlled clinical trials who became pregnant.

Well, those clever folks at FDA added a couple of things to the BELVIQ approval that might do two things. The first is a warning that women of child bearing potential should not take BELVIQ. If I were FDA, I’d try and find a way to monitor how many women and their physicians paid attention to that warning. Should be relatively easy to collect that information. If they find a significant pregnancy rate in women taking BELVIQ, they know the warning is not enough – all this done without jeopardizing an unborn child. The second thing that the FDA did was to recommend that the DEA assign a control classification to BELVIQ. Whether the DEA will do this is unknown at this time. If they do, there is a made to order distribution control for QNEXA should they decide to do it.

If your looking for the bottom line that I normally provide, this is it – if I had to lose 40 pounds in 2 years and had only the choice of waiting for QNEXA or diet, I’d start giving up the cupcakes tomorrow!

QNEXA Advisory Committee 2012

On Wed, Feb 22, 2012, the Metabolic and Endocrine Advisory Committee will meet once again to discuss the Vivus QNEXA NDA for the treatment of obesity. This Advisory Committee met in July of 2010 to discuss this same NDA.  Several members of the earlier Advisory Committee are returning either as full AdComm members or as temporary members.

The 2010 AdComm voted 6 to 10 against recommending approval for QNEXA.  The reasons given were primarily safety concerns in the areas of neurological/cognitive, cardiovascular, metabolic acidosis and teratogenicity and the need for studies in a broader population of patients.  The sponsor has responded to the concerns raised and has included a 1 year extension of one of the pivotal Phase 3 studies which measured both efficacy and attempted to address the safety concerns.

 Efficacy

This is another example of a company doing more and proving less.  The one year extension study was flawed.  The FDA stated that the selection process for patients entering the study was biased and the results should be considered “observational”.  None the less, the observation made is that there is no benefit from continuing patients beyond one year on QNEXA because even on the highest dose, patients start to regain the weight they lost in the first year.

Safety

NOTE: At 2010 AdComm, the Committee consistently noted that for each of the concerns they had, the risk in a broader population was unknown.  The new 2 year data do not represent a broader population but rather a subjective selection of patients from the 1 year study, the results of which the FDA calls “observational”.  I think “observational” means “we’re sorry you took the time to assemble these data because we had to take the time to “look” at it”.

Metabolic acidosis.  2 year safety cohort showed same reduction in serum bicarbonate.

Cardiovascular risk.  The FDA concluded that while the results were “directionally favorable”, its unknown what would happen in a high risk population or during chronic use.  Sounds like a limited indication, if approved at all, and more work to be done.  But what kind of work?  We won’t know and the sponsor won’t know until after the March AdComm which will be addressing the specific issue.

Suicidal/cognitive effects. 2 year extension did not report any additional concerns about suicidal tendency.  Probably didn’t answer original questions either.  The incidence of cognitive related adverse events was the same in the 2 year study as reported in the 1 year study.

Teratogenic effects.  There is no doubt, the topiramate component of QNEXA is a teratogen.  The sponsor agreed and amended the application to provide for a warning against use by women of child bearing potential.  The FDA responded with the rejection of their proposed labeling.  Why?  Probably several reasons.  One of which is if they excluded women of child bearing potential, the pivotal trials would be invalid as the majority of patients in the studies were women.

I’m surprised that the bulk of the questions from the FDA focus on the teratogenic effect.  I’m surprised that the Risk Management review says that this is a concern for the patients taking topiramate for epilepsy.  What is the problem people?  Go back to FDA 101 – its all about benefit risk.  Topiramate for epilepsy has one benefit risk while topiramate for obesity has another benefit risk.  As a fraction, the former is 10/5 while the latter is 1/5.   But that’s a problem for the FDA to work out for approval.

For the Advisory Committee, lets summarize, comparing what we knew after 2010 and what we know now:

-efficacy – no improvement in weight loss in second year, in fact, weight gain.

-metabolic acidosis – no new data, its still an unknown in broader population

-suicidal/cognitive – no new data, its still an unknown in broader population

-cardiovascular – no new data, its still an unknown in high risk patients and broader population

-teratogen – no new data and company acknowledges teratogenicity.  Risk management program currently seems less stringent than controls the sponsor used in controlled clinical trials and they couldn’t make that work.

I doubt the Advisory Committee will be as generous with the “yes” votes as they were in 2010.

PDUFA Date dapagliflozin

Well, the FDA has ruled on the AZN / BMY drug dapagliflozin for the treatment of diabetes.  It comes as no surprise that they feel the benefits do not outweigh the risks.  As was pointed out here in July 2011, the unknowns about safety that were also raised by the Advisory Committee, make for a difficult approval.  The only good thing that can be said for this new class of drugs is that the FDA has set the bar for approval.  Those that follow AZN and BMY with NDA submissions are well advised to clear the bar.

PDUFADate.com 2012

As we look back on the last 18 months, we are very pleased with the steady increase in visitors to our website.  We attribute this to the needs of the financial community to seek as many opinions as possible before they make their recommendations or decisions for their clients.  We are pleased that many of you keep coming back to us for help with these decisions.  You are returning because of the high degree of success we’ve had with our opinions on FDA Advisory Committee deliberations and ultimate outcome of FDA actions on pending applications.

Since the initiation of our website, we have had a limited offering of information.  We have provided a short term listing of FDA activities, either Advisory Committee Meetings or PDUFA Dates.  We have provided our opinions on some of these Advisory Committee deliberations and our opinion on some PDUFA Date actions.

As we look forward to 2012, we are evaluating enhancements to the website that we will introduce during the first quarter of 2012.  Some of these include a complete list of the FDA Advisory Committee calender with a link to the Briefing Documents as soon as they become available. In the past, we limited our opinions to those that seemed to have very clear outcomes, even though on several occasions they were contrary to the majority of opinions being expressed.  In some cases, we weren’t sure of the outcome and didn’t provide an opinion.  We have heard from some of our visitors that such a “non-decision” would be valuable for them.  Therefore, in response to your need, we will provide more opinions, some of which may state that we don’t know the outcome.  As in the past, we will provide our rationale.

We are also evaluating the addition of a resource center which will provide a listing of all drugs that we are aware of that are pending approval at the FDA.  Included in this listing will be what we know about actions that may have been taken by regulatory authorities around the world.  We are considering also, a separate listing in the resource center of drugs that are in Phase III development.

From time to time, we may go outside of the boundaries that we’ve established for PDUFADate.com by providing an opinion on broader issues facing the Pharmaceutical Industry.

One of the most exciting additions to the website will be the addition of a Reader’s Forum.  Readers will be provided with an opportunity to ask questions or make comments that can be responded to privately or to the public.

Transcept INTERMEZZO PDUFA Date

Transcept Pharmaceuticals (TSPT) is getting ready for it’s third Annual PDUFA Date coming up for INTERMEZZO for insomnia on Nov 27, 2011.  I think the results will be the same.  Why?  Because if you keep doing the same thing (submit NDAs with the same data) you can expect to get the same result – NFC from the FDA – Not Favorably Considered.

The FDA told them they had a problem with the dose in women, ie, it might be too high and there might be some carry over effects upon awakening that could present a problem.  In other words, the benefit risk ratio was tilted in the direction of risk.  So, the company lowers the dose in women by half, reducing the risk.  But what about the benefit side of the equation if you reduce the dose by half?  I don’t think they have the adequate and well controlled study on that.  So, we’ll probably get a chance to comment on this again next year when they celebrate their Fourth Annual PDUFA Date for this drug.

EYLEA PDUFA Date opinion

Regeneron (REGN) is probably still basking in glory of their recent unanimous recommendation from the Advisory Committee for EYLEA (aflibercept opthalmic solution) Opthalmic Solution for the treatment of age related macular degeneration.  The company should now be directing its focus on the upcoming PDUFA Date of Aug 20, 2011 and anticipating an approval.

BRILANTA PDUFA Date

The PDUFA Date for Astra Zeneca‘s Brilanta is still a ways off, not until July 20, 2011 but we think it’s safe to call this one an approval.  AZN has had it’s problems with this application since the original submission in 2009.  Initially rejected by the FDA for a variety of problems including manufacturing issues, their latest CRL only cited a reanalysis of some of the clinical data and required a post marketing safety plan, REMS.  We think that AZN has probably solved both issues with the FDA.  The earlier approval this year by the European Authorities and the approval earlier this month by the Canadians probably reflects the reanalyzed data.  We wouldn’t be surprised if the approval came before the PDUFA Date.

YERVOY (ipilimunab) PDUFA Date

The PDUFA Date of March 26, 2011 is rapidly approaching and Bristol-Myers Squibb is justifiably hopeful that it will mark the approval of YERVOY (ipilimunab) for melanoma.  The FDA gave this drug a priority review status but then delayed the PDUFA Date for 3 months for some reanalyses.  This time should be the charm.  Why?  It’s a cancer drug that shows a survival benefit and that’s the name of the game with the FDA – show me the survival!!

BENLYSTA – PDUFA Date

Last month, the FDA Advisory Committee recommended approval for the HGSI/GSK drug BENLYSTA for the treatment of lupus, the first new treatment for lupus to come down the road in decades. We pointed out the difficulties the FDA would have with conveying the safety and efficacy information into a meaningful package insert.  The Committee either looked beyond that or thought the regulatory obstacles facing the FDA as they try to write the package insert could be easily overcome.  While we provided some wording suggestions at the time, we don’t think the FDA can resolve this issue in a timely manner, certainly not before the PDUFA Date of December 9, 2010 unless HGS and GSK both want this approval so badly that they roll over with a very restrictive package insert.