Archive for February 2012

QNEXA Advisory Committee follow up… Think about this

I’ve had a few days to think about this and still have a difficult time understanding the Advisory Committee vote. I admit that I didn’t see this coming. Maybe I should have. After all, this committee (with different members) gave a thumbs up to CONTRAVE. And what happened with CONTRAVE? The FDA went back to the basics of the drug approval process, the basics of benefit risk, and determined that the sponsor had not satisfied the regulatory requirements.

Will the same thing happen with QNEXA? I don’t know what the FDA will do, but I do know what they should do. Efficacy doesn’t seem to be an issue although there doesn’t seem to be any additional weight loss after 1 year of treatment. With the unanswered, it seems likely that if approved, use beyond one year will be limited.

But let’s look at the safety issues. The two biggies are sitting right out there – cardiovascular risk and teratogenic potential in women of child bearing potential. Both of these are unknowns at this time and both can be answered. The question for the FDA is whether the answers should come before approval or after approval.

Teratogenic risk: QNEXA is a teratogen. The population at risk has a high percentage of women of child bearing potential. The component responsible for the teratogenic risk is already available for the treatment or migraines and epilepsy in a population that contains women of child bearing potential. The issue here is not the approvability of the drug but rather the adequacy of the REMS program and the labeling. Can the FDA and the sponsor work this out before the PDUFA Date?

Cardiovascular risk. The FDA has raised this issue in both of their Briefing Documents. The previous Advisory Committee had this as one of the major outstanding issues they used to support its 6-10 vote against recommending approval. The FDA is concerned enough about cardiovascular risk with obesity drugs to call for another Advisory Committee meeting with this as the sole topic for discussion next month. Now, the interesting thing is that the upcoming Advisory Committee meeting is going to be another meeting of the Endocrine Metabolic Drugs panel, the same panel that just recommended approval for QNEXA. The FDA will probably invite a lot of cardiologists, more than were at the QNEXA meeting. The cardiologist vote for QNEXA was split, one for, one against approval. The negative vote was very negative. It is unlikely the FDA will make any decision about resolving the cardiovascular risk associated with QNEXA until after the March Advisory Committee. If the Committee continues to support the current FDA reequirement that studies that rule out cardiovascular risk must be completed before approval then the decision to be made by the FDA is obvious. If however, the Committee recommends that in some circumstances these studies can be conducted post approval, the question then becomes whether the FDA and the sponsor can work this out before the PDUFA Date. They would have to agree to the protocol for such a study and agree on labeling that identifies the absence of information that defines the population at risk.

I’m of a view now that QNEXA will be approved for the treatment of obesity. The questions of when and with what kind of a label still remain. It is unlikely it will be approved at its PDUFA Date. How long after the PDUFA Date is a question that can only be answered after the March Advisory Committee meeting. A point to keep in mind – while we are focusing on the approval of QNEXA, the FDA is also thinking about the precedent it will set for other drugs in the review/development pipeline.

QNEXA Advisory Committee follow up

I have to compliment the folks at Vivus, they did a great job.  Good enough to convince the Advisory Committee to recommend approval.  The big question is whether they convinced the FDA.  We’ll find out in a couple of months.

The AdComm does require a comment though.  If I had heard the commentary from the AdComm members without knowing their vote or the overall vote, I would have thought the overall outcome would have been negative.  Almost everyone of them expressed reservations about the CV signals and a concern about the teratogenicity. They used words like “trepidation”, “inconclusive”, “difficult decision”, “reservations” and the “risk is real”.  And those were the panelists who voted YES. Most interesting were a couple that deserve noting.  Regarding benefit risk, one panelist noted that because the drug is not 100% effective and presumably because those who will respond are not predictable, there will be patients who have the risk but not the benefit.  The most unusual comment from a YES voter who had reservations about the teratogenic potential was “the baby gets no vote”.  Dr. Lauer seemed to reflect my opinion best.  He viewed the results as surrogate outcomes…based on hopes not data and reminded everyone of previous similar enthusiasm for antiarrythmics that looked good but killed people.

It will be interesting to see which words resonate with FDA, the YES votes or the reservations.

NORTHERA (droxidopa) Advisory Committee Meeting

On Thursday, Feb 23, 2012, the FDA Cardiovascular and Renal Drugs Advisory Committee will meet to discuss Chelsea Therapeutics NORTHERA (droxidopa) NDA for use in the treatment of some very specific aspects of orthostatic hypotension.  Chelsea asked for and was granted Orphan Drug designation.

The drug seems to have a positive short term effect but there are a lot of serious concerns about safety, both from data that have been reported in the clinical trials and from post marketing reports from Japan where it is approved although at a lower dose.  At least equally important to making a decision are the unanswered questions about efficacy and safety.  The FDA has listed the known problems as well as the deficiencies in the data base in their briefing document and conclude that the drug is not ready for approval.
The Advisory Committee will likely agree with the FDA conclusion on this drug.

Forest Laboratories/Almirall aclidinium Advisory Committee Meeting

On Thursday Feb 23, 2012, the FDA Pulmonary-Allergy Advisory Committee will discuss the Forest Laboratories, Inc./Almirall S.A. aclidinium NDA for the treatment of COPD.

I find it interesting when the FDA includes the regulatory history in the Briefing Document, probably because it usually focuses right in on the issues.  In this case, it shows that the sponsor was given some advice on how to develop the drug by the FDA and chose to ignore it.

The FDA early on “suggested” that peak FEV and FEV AUC were the appropriate measures for a COPD trial.  The sponsor chose FEV trough.  Using this FEV trough, the sponsor provided an improvement of 60 ml vs the 150 ml they had offered in the Phase 2 trials.  The sponsor offered 1800 patients for safety at the recommended dose which the FDA said might be ok if the data were robust.  When the sponsor and FDA agreed that the 200 mcg dose was inadequate, the sponsor went back and did 2 more Phase 3 trials and then offered the FDA less than 1800 patients at the recommended dose of 400 mcg.  In this meager data base, there were patients with cardiovascular problems.

Anticholinergic drugs carry a risk of cardiovascular problems.  This is an anticholinergic drug.  The data base was too small to evaluate the cardiovascular risk of patients taking the recommended dose as chronic therapy.

The sponsor has probably failed on the efficacy measure with the FEV trough measure, hence the question from the FDA on the “clinically meaningful benefit” of the 400 mcg dose.  The sponsor failed to provide a data base that could adequately answer the question about cardiovascular risk for this anticholinergic drug. The sponsor will fail to gain the approval of the Advisory Committee.

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.

QUENTZA (capsaicin) FDA Advisory Committee Meeting

On Thursday Feb 9, 2012 the FDA Anesthetic and Analgesic Advisory Committee will review the supplemental application from Neurogesx for QUTENZA (capsaicin).  The company is asking for approval of an additional label claim for treatment of pain associated with HIV neuropathy.  The drug already has an approved claim for treatment of pain of post-herpetic neuralgia.

The company is seeking approval of the 8% formulation being used for 30 minutes.  The drug was tested at doses of 4% and 8% for durations of 30, 60 and 90 minutes. There are only two problems with this application.  The first is that the studies showed little or no dose response.  This is not good if one is seeking an approval.  The second problem is that the drug only showed a benefit when administered for 90 minutes.  This is not if you are seeking a treatment duration of 30 minutes.

The FDA made the effort in their review to cite the Regulations for effectiveness.  This is not good either.  I guess that really makes three problems!

XGEVA (denosumab) Advisory Committee Meeting

On Wed, Feb 8, 2012 the FDA Oncology Advisory Committee will discuss Amgen‘s supplement to their approved BLA for XGEVA (denosumab) for treatment of men with castrate-resistant prostate cancer at high risk of developing bone metastases.

This Advisory Committee discussion and the ultimate FDA approval decision comes down once again to the basic benefit risk decision.  On the benefit side, treatment with denosumab did not result in an improvement in overall survival or progression free survival but it did improve bone metastasis-free survival (BMFS) and time to first bone metastasis, both by about 4 months.  On the risk side, the incidence of osteonecrosis of the jaw with denosumab increased by about 5%.  So, the basic benefit risk question is does the 4 month improvement outweigh the 5% increased risk?

The other significant question raised by the FDA appears to boil down to whether treatment with denosumab in this setting offers any advantage versus “prevention of skeletal related events in patients with solid tumors metastatic to bone”, the approved indication.

The FDA review appears to be on the negative side of neutral.  While the company met the primary endpoint, the FDA review points out that at meetings with the company, the FDA noted that “overall survival, patterns of metastases, and the development of symptomatic metastases will be important review issues”.  There was no advantage in overall survival.  Also, of significant note is the statement in the FDA review that the study was not conducted under a Special Protocol Assessment, meaning there is no “contract” for approval just because the primary endpoint (improvement in BMFS) was met.