Archive for the ‘William Kennedy’ Category.

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.

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!

Diet Drugs in 2012

We’ve had several questions from readers asking if our opinion on the diet drugs that failed in 2011 has changed. Specifically, will Qnexa (or by extrapolation) or any of the other diet drugs have an easier go of it the next time around, ie, is the Cupcake Commentary still valid?

We’re going to take a slightly different approach with this posting and give our readers an insight into one of the changes we are thinking about for 2012 and beyond. We’re going to provide a more detailed commentary in this, the first response to our new feature, the Readers Forum.

Let’s start with the basic criteria for approval from the FDA Guidance on Diet Drugs. The draft guidelines from 2007 state that to prove efficacy, a diet drug must have two adequate and well controlled studies that demonstrate:

After 1 year treatment either:

  • There is a difference of 5% or greater between placebo and active drug OR
  • Greater than 35% of patients treated with drug have a difference of greater than 5% from baseline and twice the difference from placebo.

In earlier postings, we pointed out that the 5% difference is a very modest decrease in weight for a year and is comparable to having one less cupcake a week for a year for a 200 pound person. (200 lbs x 5% = 10 pounds; 10 lbs/52 weeks = 0.192 pounds per week, or about 3 oz, the size of a typical cupcake).

Let’s look at the data that were reported in the Briefing Documents prepared by the sponsors and the FDA for the Advisory Committee meetings that were held to discuss the diet drugs submitted for approval.

DrugEfficacySafety
LorqesFailed 5%- Tumorogenicity
QnexaPassed 5%
- Depression
- Memory Loss
- Metabolic Acidosis
- Increased HR
- Potential teratogen
- Lack of CV Date
ContraveFailed 5%
Passed 35%
- Increased SBP, DBP and HR
- MACE Inadequate
- Psychiatric AE

Let’s look at the alternatives to diet drugs. On one side are the diets and exercise that offer limited benefit and little risk. From purely anecdotal reports, if would appear that the General Motors Diet is the most successful. Many have not heard of this diet because nobody can make any money writing about it. It is the diet that has been used by the General Motors health professionals for years and is freely available on the Internet. Success is often reported as 5% weight loss in a week and safety is not an issue. Attendant with the success is often a change in eating habits.

On the other side of the diet drugs is gastric bypass surgery and its alternative, the stomach band. Success is reported as high as 30% weight loss in a year, a normalization of the diabetic state and a change in eating habits. Safety concerns include those associated with surgery and potential long term metabolic changes. It should be noted that this extreme surgical intervention is limited to those identified as obese and there is significant pre-screening qualification before the surgery and extensive monitoring afterward.

So, as a generality, diets can be said to be the least effective (as measured by sustained weight loss) for the majority of people but the safest, while gastric bypass surgery is currently the most effect but carries the most danger. Diet drugs tend to be between these two extremes, marginally more effective than diet alone but significant potential for more adverse effects.

Of course, the patient populations of these three treatments tend to be different. Diet and exercise is a treatment available to anyone, diet drugs for patients who need a bit more than the diet and exercise and bypass surgery generally reserved for those described as obese.

The FDA and its Advisors must determine if the diet drugs are safe and effective for the intended population, that is, those who fail diet and exercise alone but not so obese that they require bypass surgery.

Is there a regulatory precedent for this kind of treatment and this kind of population? I say yes. Recall the acne treatment isotretinoin or ACCUTANE as it was first marketed. Acne is a disease that can be treated with non-prescription drugs in the mildest condition, prescription drugs for those who don’t respond to the non-prescription drugs and for the most severe forms of acne, treatment with ACCUTANE is effective. Also like the use of diet drugs, acne treatment has a certain cosmetic component to it. By that I mean while there are certainly positive health components to treating both obesity and acne, treatment of both also usually results in a more attractive individual.

The ACCUTANE approval was held up because, like some of the diet drugs, it produced birth defects. The conventional wisdom whispered but never overtly expressed at the time was that this was a time bomb waiting to explode. One potential patient group was women of child bearing potential and clearing up acne had the potential to make their child bearing potential greater. Very restrictive labeling was proposed and rejected. The approval of ACCUTANE was delayed while this aspect of benefit risk was debated. When it was approved, and to this day, it carries a severe restriction requiring that women of child bearing potential have 2 negative pregnancy tests and be using 2 methods of birth control before it can be prescribed to them.

There is no reason to believe that the FDA has reduced its standards for drugs that have a potential for birth defects, especially if the drug has the potential for wide spread use in women of child bearing potential. Like ACCCUTANE, diet drugs have the potential to to make the child bearing potential of women of child bearing potential more potential.

Vivus has resubmitted its NDA for QNEXA with requested additional cardiovascular safety data to address issues that arose during the previous NDA review. These data will be reviewed at an upcoming Advisory Committee in February when the committee will have the opportunity to see the FDAs view of these limited data. It is likely the FDA will also ask the committee to comment on QNEXA use in women of child bearing potential, perhaps the reason the FDA has not insisted on included this population as a contraindication. Or perhaps they just feel it doesn’t make any difference because the drug still doesn’t have a benefit risk ratio that justifies approval.

NEXT TIME: Is it time for the FDA to revise the Guidance document for drugs used to treat obesity?

XARELTO Advisory Committee Follow-up

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.

XARELTO (rivaroxaban) Advisory Committee Meeting

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.

AFINITOR (everolimus) Advisory Committee Meeting

On Tuesday, April 12, 2011, the FDA Oncology Advisory Committe will hear Novartis and the FDA discuss the application for AFINITOR (everolimus) in the treatment of patients with advanced neuroendocrine tumors of GI, lung and panreatic origin.  The drug is already approved for the treatment of advanced renal cell carcinoma and after the Advisory Committee meeting, I think that Novartis will have to settle for retaining that indication for the time being.

The FDA has raised questions about the value of progression free survival in predicting overall survival as it usually/always does with oncology drugs, as well as questions concerning the censoring of certain patients and whether the 2 Phase 3 trials support each other.  Novartis will argue that the terms of the Special Protocol Assessment allowed for progression free survival as a valid endpoint.  And, here is where they lose the argument.  FDA will point out as they did at the Pre-NDA meeting that Novartis protocol amendments have made the SPA invalid.  It is unlikely that the FDA will give in on the sanctity of the SPA contract.  It is a contract between industry and the FDA, binding on both.  In fact, the value of the SPA to the industry is the binding of the SPA.  If the FDA bends on this, Novartis will win the approval and FDA will be able to say in the future that FDA can invalidate their agreements made under the SPA.

This is not the drug, nor the indication to test the contract.  AFINITOR is on the market already and patients have access to it if their physicians feel it necessary for their treatment.

DIFICID (fidaxomicin) Advisory Committee

On Tuesday April 5, 2011 the FDA’s AntiInfective Advisory Committee will discuss Optimer Pharmaceutical’s (OPTR) drug DIFICID (fidaxomicin) for the treatment of adult Clostridium difficile.  The sponsor seems to have conducted adequate studies demonstrating that the disease and the organism are both present at the start of the study and the disease and organism are not present after treatment.  The FDA Briefing Document seems to pose no threat to the approval of this drug.  The company has shown that the drug is both safe and effective in the indicated population.  While the FDA reviewer took issue with some of the outcomes, the conclusion is identical to that of the sponsor.

There are really only 2 issues which will warrant discussion.  The first is the second question posed to the Advisory Committee related to recurrence.  If this question is intended to provoke a discussion on resistance, the result can only be – the bug will eventually win.  Bacteria have always found a way to become resistant and they always will.

The second discussion topic might be the non-inferiority analysis.  I think this will be academic, brief and in favor of the sponsor.

FDA Advisory Committee – LAMICTAL XR



On March 10, 2011 the FDA will ask the Peripheral and Central Nervous System Drugs Advisory Committee to vote on the use of GlaxoSmithKline LAMICTAL-XR as monotherapy for partial seizures.  Listed on the undercard of the main event, is a discussion and series of questions that the FDA wants the Committee to address related to the use of historical controls.
 
The first question that the FDA is asking is whether it is ethically acceptable to conduct placebo-controlled studies in this patient population.  To me, the answer is as obvious as if the question was asked by any FDA Division of any Advisory Committee about any disease that has FDA approved drugs available to treat the disease.  That answer is NO.
 
However, I don’t understand the rest of it.  And, by the “rest of it” I mean the questions and the development strategy that led to the questions.  LAMICTAL is approved as an immediate release product as monotherapy for the treatment of partial seizures.  Why wasn’t it sufficient to do a bioequivalence study with some clinical parameters?  I understand that a “non-inferiority” trial might have been prohibitively large but the difficulties listed by the FDA with the French et al approach is like scoring a heavy weight title fight by who had the fewer missed punches.
 
That being said, it would appear that the FDA review is relatively positive with the conclusion being that the data are adequate for approval.  Let’s hope the Committee doesn’t get confused with all missed punches and can focus on the fact that all this is about is an extended release formulation of a drug that is already approved for the indication as an immediate release product.