Posts tagged ‘FDA’

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.

FDA Advisory Committee Schedule

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.

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?

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.

AZILECT (rasagiline) Advisory Committee Meeting

On Tuesday, Oct 17, 2011 the FDA’s Peripheral and Central Nervous System Advisory Committee will discuss TEVA‘s NDA for AZILECT (rasagiline) for use in slowing the progression of Parkinson’s disease.  AZILECT has been approved since 2006 for treating the signs and symptoms of Parkinson’s disease.

The FDA’s Briefing Document raises multiple regulatory issues which seem to support a negative view on approval by the FDA.  These include study design, adherence to protocol (especially regarding the analyses) and interpretation of the results. The FDA conclusion seems to be “We don’t know if there is an adequate study that can be done.  We don’t think the major study was designed to support the indication.  The major study did not adhere to the planned statistical analyses.  We think that the other study was even less well designed to support the indication.  The results of both studies do not support the indication for disease modifying.”

I think the most interesting discussion will be around Dr. Paul Leber’s paper on the design of trials to study this indication.

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.