Posts tagged ‘PDUFADate.com’

We’re Back!

After a long hiatus, we are pleased to announce that we will begin posting opinions about FDA events again.  We also would like to announce the addition of  two new contributors to our site, Dan Heathwood and Tim Shields.  Both are private investors with previous experience working as research analysts for some well known investment firms.  Their past contributions outside of pdufadate.com  have  helped translate our opinions into sound stock trading advice.   Our first post will probably deal with Durata Therapeutics (DRTX) as we continue to receive numerous emails about dalbavancin.

There will be lots of changes to our site so keep checking back.

UCERIS PDUFA Date Delay

This past week, the FDA told Santarus, Inc. that it was extending the review period for their ulcerative colitis drug UCERIS by 3 months.  The FDA extended the PDUFA Date to January 16, 2013 because they need more time to complete the review.

I usually don’t comment on share price or share price moves but I’m making an exception here.  The stock dipped on this news.  I can’t figure these things out.  It might not be negative news.  I don’t think the FDA has a mind set that says “This application won’t be approved but we need more time to review the bad data”.  I think the contrary holds.  If the FDA sees some merit in an application, it will take the extra time to support the approval.  There is still a PDUFA report card and extending the review period for a drug that will eventually be rejected doesn’t make sense.

The Last Days of the Diet Drug Dilemma

Those of you who read our Special Report on Diet Drugs got a heads up on both the extension of the QNEXA PDUFA Date and the easy time that LORQESS had with the FDA Advisory Committee last week.  But now it’s crunch time and the folks at Vivus and Arena Pharmaceuticals are supplementing their diets with fingernail sandwiches.  Arena has the shorter wait at this time, June 27, 2012 is still their PDUFA Date for LORQESS.  By virtue of the extension, Vivus has to wait until July 26, 2012.

Neither the FDA nor the Advisory Committees have questioned the efficacy of either drug.  Neither set of reviewers have tried to say one is more efficacious than the other.  I agree and would call them equally efficacious.

Both drugs have reported or perceived cardiovascular side effects.  According to the Advisory Committee earlier this year, such drugs should be required to have cardiovascular studies performed before approval.  However, both drugs were submitted for approval and under review when the recommendation, and it is only a recommendation, by the Advisory Committee was made.  That being said, the FDA has a certain degree of leeway in forcing this requirement as an approval requirement.  In my opinion, the FDA will give both companies a break and allow the required study to be done as a condition of approval.  It will be the most closely watched event since the OJ trial.  One might think that QNEXA has the leg up on this because they went to the Advisory Committee first, but in this case, one would be wrong.  Both companies got the information at the same time – from listening to the Advisory Committee live and in person.  Who has the edge on having the protocol in final form?  I don’t know and neither does anyone else except maybe the FDA and I heard they ain’t talking.

FDA doesn’t have to talk about the cardiovascular protocol race because the race isn’t about the cardiovascular side effects, its about the teratogenicity risk.  FDA is breathing a sigh of relief with the data from Arena and the positive vote from the Advisory Committee for LORQESS.  The pressure is off – they have a viable diet drug alternative to QNEXA to satisfy those screaming for a new drug.  And they have an alternative that is not a teratogen.  Even if LORQESS gets an extension of the PDUFA Date from FDA to tidy up their cardiovascular study protocol, they will still be ahead of Vivus who has a somewhat longer struggle with the teratogencity issue.

Diet Drug Special Report is Available

With the Vivus‘ QNEXA PDUFA scheduled for April 17,2012, we have created a special report that reexamines all of the obesity drugs that have been reviewed by the FDA and the Advisory Committee since 2009 to determine if any additional insight could be gained regarding the expected action the FDA will take on QNEXA. The report can be purchased by clicking here or by going to http://www.pdufadate.com/premium-reports.

We changed our automated delivery method with the NORTHERA report so when you do purchase the Diet Drug Special Report, please make sure your spam filter accepts email from pdufadate.com.

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.

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.

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.

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.

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?

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.