Archive for the ‘Advisory Committee’ Category.
On April 5, 2012, the FDA Reproductive Health Drug Advisory Committee will discuss the mirabegron application from Astellas for the treatment of overactive bladder. Astellas already has a drug on the market for this indication, VESIcare.
The FDA Briefing Document notes that the drug achieved statistical significance in all 3 of the Phase 3 trials submitted and the secondary efficacy endpoints were consistent with efficacy.
Regarding the safety of mirabegron, the FDA has raised several concerns. There is an increase in both heart rate and blood pressure noted in both Phase 1 and Phase 3 trials that seems to be greater with higher doses. The FDA further states that the size of the data base (presumably too small) prevents them from further evaluation of this observation so the question remains open. They also note an increase in neoplasms but this is probably not an issue as they seem to occur at high doses and seem to consist of neoplasm common to adults. Hepatotoxicity, hypersensitivity and urinary tract infections are also noted but are infrequent and probably not an issue either.
This leaves only the cardiovascular safety issues that should be a concern when considering the benefit risk for this product. How will the Advisory Committee respond to the FDA question regarding benefit risk for this product?
We think there will be a positive vote but it will be close. Why? While the efficacy is positive using the statistical significance measure, the clinical significance of the improvement seems marginal. In fact, if one compares the numbers reported by Astellas in the VESIcare package insert, it appears that mirabegron has slightly inferior efficacy. There are patients who should not take VESIcare that seem to be indicated for mirabegron, so the Urologists on the Advisory Committee may see this as a necessary drug for those patients. The big issue will really be how seriously the FDA takes the cardiovascular risks and how the Advisory Committee responds to those concerns.
It will be close, but we think the Advisory Committee will recommend approval.
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.
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.
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.
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.
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!
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.
As promised earlier, we are providing a more detailed listing of upcoming FDA Advisory Committee Meetings.
Of particular interest, Vivus‘s QNEXA is scheduled to be reviewed on Feb 22, 2012 by the Endocrinologic and Metabolic Committee for weight management. Equally important, the FDA has scheduled another meeting of the Endocrinologic and Metabolic Committee for March 28-29, 2011. Could it be that we might hear some discussion on revised guidelines?
Jan 30-31, 2012 Pediatric Advisory Committee Meeting
- The Committee will discuss the status of the development of a number of drugs for pediatric use.
Feb 8-9, 2012 Oncologic Drugs Advisory Committee Meeting
The Committee will discuss:
- XGEVA (denosumab) by Amgen for castrate resistant prostate cancer.
- DACOGEN (decitabine) by Eisai for acute myelogenous leukemia.
- PIXUVRI (pixantrone dimaleate) by Cell Therapeutics for Non-Hodgekins Lymphoma
Feb 10, 2012 Cellular, Tissue and Gene Therapies Advisory Committee Meeting
- No products are currently on the schedule for review.
Feb 10, 2012 Neurological Devices Panel Advisory Committee Meeting
- No products are currently on the schedule for review
Feb 22, 2012 Endocrinologic and Metabolic Advisory Committee Meeting
- The committee will discus QNEXA by Vivus for weight management
Feb 23, 2012 Cardiovascular and Renal Drug Advisory Committee Meeting
- The committee will discuss NORTHERA by Chelsea Therapeutics for neurogenic orthostatic Hypotension.
Feb 27, 2012 Dermatologic and Ophthalmic Drugs Advisory Committee Meeting
March 12, 2012 Arthritis Advisory Committee Meeting
March 14, 2012 Pharmaceutical Sciences and Clinical Pharmacology Advisory Committee Meeting
March 28-29, 2012 Endocrinologic and Metabolic Advisory Committee Meeting.
Yesterday, the FDA’s Advisory Committee voted 9-2 in favor for recommending approval for XARELTO. This is a remarkable outcome considering the very negative Briefing Document released by the FDA in advance of the meeting. Let me rephrase that, it was not just a very negative Briefing Document but probably the most negative Briefing Document I’ve ever seen. The J&J team must be congratulated.
But, how could the FDA interpretation of the data be so different from that of the sponsor, their advisors and the Advisory Committee members? With such a positive vote by the Advisory Committee and such a negative review by the FDA, somebody seems to have gotten it very wrong. At the 4,000 ft level, there appears to be a clue. The overtone of the FDA review can be seen to have the flavor of “in a perfect world” while the contrary view of the sponsor and their experts emphasizes the “real world” experience of treating these patients. Does this sound familiar? To me it sounds like the same debate the 535 perfect-worlders in the principality of the US Congress are having with the real-worlders who elected them.
The approval of XARELTO for this indication is ultimately still in the hands of the FDA and they will make their decision on their view of the benefit/risk of this product and the ability of the sponsor to provide adequate labeling for its safe and effective use.
The application for XARELTO (revaroxaban), the J&J drug that was developed for it’s anti-clotting properties in preventing strokes is to be reviewed by the FDA CardioRenal Drug Advisory Committee on Thursday, Sept 9, 2011. Those interested in the FDA view of the application need read no further than the summary of the FDA Briefing Document to learn that the FDA Medical team has significant reservations on both the safety and the efficacy of this drug. How significant you ask? So significant that if I were advising the company, I’d tell them to cancel the Advisory Committee meeting. The FDA review started with a comment about readiness to issue a Complete Response Letter, that’s how serious! The FDA review has requested at least one additional study, that’s how serious. The FDA has said that any drug that expects to compete with Warfarin in these patients better be as good as Warfarin, that’s how serious. It looks like the FDA thinks that XARELTO performs at less than 70% of the efficacy of Warfarin.