Archive for the ‘Advisory Committee’ Category.

Dapagliflozin Advisory Committee Meeting

On Tuesday, July 19, 2011, Bristol-Myers Squibb Company (BMY)  will present their case before the FDA Advisory Committee for dapagliflozin for the treatment of diabetes.  This drug is the front runner in a new class of diabetes drugs called SGLT2-inhibitors which reportedly enhances excretion of glucose via the kidneys.  With such a unique mechanism of action, attention naturally focuses on intact kidney function for a reliable drug effect.   Herein lies my first issue.  BMY enrolled over 6000 patients in the trials with over 4000 on dapagliflozin.  They included a full range of patients with kidney disease – normal, mild, moderate and severe.  As would be expected, those with severe kidney failure didn’t do well on the drug.  What is surprising is the response of the patients with moderate kidney failure.  Using a post hoc analysis, they split the “normal” moderate range of roughly 30-60 mL/min/1.73m2 in half and showed, as would be expected, those with better kidney function performed better.  The question is not so much the post hoc analysis (everyone does it to a certain degree) but rather, is it a reasonable to redefine “moderate” kidney function to gain drug approval?  If not, they will have to abandon all of the moderate kidney function patients and label the drug for normal and mild kidney function patients.  Is this a risk the FDA wants to take?

The efficacy of the drug in these normal and mild kidney function patients seems adequate, so we don’t have to dwell on it.  But, we do have to look at the other safety signals that the FDA wants the Advisory Committee to address.  While the FDA agrees that there is no CV risk, they curiously state that “a CV outcomes trial is necessary to better charaterize CV safety…”.  There is at least one case of dapagliflozin induced liver injury cited by the FDA reviewer.  There are 9 cases of bladder cancer on drug compared to 1 on control, and 9 cases of breast cancer on drug compared to 1 on control.

The FDA has only asked 2 basic questions to help them get at the benefit risk determination.  Is it an effective glucose lowering agent?  The answer to that is probably yes, in patients with normal or mild kidney disease.  Does the efficacy outweigh the risk?  The answer to this is, we probably don’t know.  The bottom line for the Advisory Committee should be there is an unknown benefit/risk ratio associated with this drug.  These unknowns about CV safety, liver injury, bladder cancer and breast cancer, not to mention the issues associated with patients with moderate kidney disease should be addressed before the drug is added to all of the other drugs that effectively treat diabetes today.

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.

Novartis Advisory Committee Meeting – indacaterol

On Tuesday, March 8, 2011, the Pulmonary-Allergy Drugs Advisory Committee will meet to discuss Novartis‘ NDA for indacaterol in the treatment of COPD.

This trip before the AdComm is one of the last steps in a long journey Novartis has had with this drug in the US.  They originally submitted the NDA for both a 150 mcg and 300 mcg once a day dosing regimen in COPD.  The FDA didn’t like the application for several reasons:

  • all other COPD treatments offer only one dose, not a choice
  • the 300 mcg dose seemed to present some safety issues without an apparent efficacy advantage.

Novartis and the FDA agreed to a program that studied a lower dose, 75 mcg once a day.
The results are in and guess what?  The FDA still doesn’t like the application for several reasons:

  • all other COPD treatments offer only one dose, not a choice
  • the 150 mcg dose seems to present some safety issues without an apparent efficacy advantage.

Looking at the efficacy data that the FDA has highlighted in their Briefing Document, it’s hard to disagree with them.  There is a very modest improvement with the 150 mcg dose over the 75 mcg dose.  The safety issues that the FDA raises are real in the mind of the FDA reviewer, therefore, they are real!

The questions posed to the Advisory Committee members come down to the same basic rationale that has guided the FDA recently:

  • Is the drug efficacious?  yes
  • Is the drug safe?  yes
  • Is the benefit risk on the positive side of neutral?  Here is where the problem is.  The FDA is saying that their perception of benefit risk is that both appear to be positive but 75 mcg is better than 150 mcg, so why do you need 150 mcg?
  • Can adequate labeling be written to guide the medical community?  Here’s the other problem for FDA.  It doesn’t see the need to give a choice of 2 doses because you probably can’t write a package insert intelligently enough to help the medical community make the decision between the two.

The questions to the Advisory Committee appear easy to answer except the dreaded c) “If not, what further data should be obtained?”

I suspect the Advisory Committee will see where the FDA is going with this and recommend approval of the 75 mcg once a day and take the 150 mcg dose off the table.  Hopefully, Novartis won’t argue to strongly for 150 mcg and take the approval.

ZICTIFA – Advisory Committee Meeting

On December 2, 2010, Astra Zeneca will present data to the FDA Oncology Advisory Committee for ZICTIFA (vandetanib) hoping to get their recommendation for the treatment of unrestable (non-operable) locally advanced or metastatic medullary thyroid cancer.

This should be an interesting discussion to watch – a study of contrasts.  While the disease is not one of the most serious cancers, the clinical trial data show a more than 50% increase in survival time BUT with a 31% incidence of serious adverse experiences compared to only 13% for placebo.  So, the balance of a significant improvement in survival will be compared with a significant incidence of serious adverse experiences will be discussed.  How does FDA feel about this?  They appear to be leaning towards approval of this drug but with some caveats.  They are asking the Committee to discuss 2 options that will help improve the benefit risk ratio.  The first is restricting the labeling to a more serious patient population than AZ is seeking.  The FDA is asking the Committee to limit use to patients with progressive, symptomatic medullary thyroid cancer.  The second option is for the Committee to discuss the evaluation of lower doses in a post-marketing study.

If AZN can provide the sub group analyses that show similar improvement in these more serious patients and also provide data showing a reduction in the incidence of the serious adverse events in patients who had their dose adjusted downward, the Committee might be just inclined to give their recommendation for approval in this limited population with more specific instructions on dosing.

VIVITROL – FDA Advisory Committee Meeting

On September 16, 2010, an FDA Advisory Committee will review Alkermes application to extend the VIVITROL indication to include treatment of opioid abuse in addition to the alcohol dependency it currently has.   When we first heard of this, we thought this was a slam dunk.  Early indicators were that the clinical trial was statistically significant and the adverse event profile was not much different from what was seen with the patients who were being treated for alcohol dependency.  But now we’ve seen the FDA Briefing document and things aren’t so clear.  For one, the application is based on a single relatively small study conducted in Russia.  In very guarded terms, the FDA has asked the Advisory Committee to determine if the study is applicable to the US patients.  Why so?  Because the patient population in the Russian study is very lean on people of color, only 2 Asians, the rest >99% are white.  So, does it represent the patient population that will use the drug in the US?  The short answer is NO.  The “margin of efficacy” (our term, not theirs) is only a 12% difference in efficacy between the placebo patients and the Vivitrol treated patients.  So, it is conceivable that if the drug is less effective in treating people of color then the “margin of efficacy” could disappear in a clinical trial population that represents the US patient population.  And that we don’t know because Alkermes didn’t consider that in setting up the trial in Russia.

It is difficult to predict with any degree of accuracy how the Advisory Committee will go but the lack of data in a representative US patient population for whom the drug is intended is a major regulatory obstacle.  If this study was done in the US, would the FDA accept the demographics?  Probably not.  Is this drug better than anything else that’s out there now for treating opioid dependency?  Is it better than immediate release naltrexone for treating opioid dependency?

Lorcaserin – FDA Advisory Committee

The FDA Advisory Committee will review Arena’s Lorqess (lorcaserin) on Sept 15, 2010 for the treatment of obesity.  It’s hard to find anything positive to say about this.  It looks like there’s still the marginal efficacy issue that was present before and the safety concerns, particularly regarding cardiovascular, are still there.  Which means Arena has done little to increase the marginal benefit risk ratio they had before.  The only question that remains unanswered is whether any of the Advisory Committee members will recommend approval.

Meridia – Advisory Committee Meeting Sept 15, 2010

Another diet drug with cardiovascular problems, another Advisory Committee Meeting, only this time it’s not a case of getting the drug on the market.  For drug maker Abbott, it’s a question of whether their data is strong enough to convince the Advisory Committee to recommend something other than withdrawal, one of 4 options the FDA has posed to the Committee.  At the other end of the option spectrum of questions, the Committee could choose that the drug is safe, effective and the package insert as it is currently written is adequate.  This is unlikely.  Data suggests a cardiovascular problem and problems don’t go away if you keep doing the same thing.  Ask Tiger Woods.  Eventually you’re going to run into a tree.
We’ve said it before, obesity generally presents with co-morbidities of cardiovascular problems, diabetes, respiratory etc.  It’s part of the package.  When there is a cardiovascular signal, we don’t think you can adequately provide labelling in a big enough black box that defines the patients at risk to the degree of confidence that will make the FDA comfortable with any of these drugs.  We think this is a close call between asking the company to produce a REMS program that provides this extra help for the prescribing physician or withdrawing the drug, i.e, limited distribution or no distribution.


The FDA Anti-Infective Advisory Committee will meet on Sept 7, 2010 to discuss the NDA for ceftaroline.  The FDA released it’s briefing document and questions before the long Labor Day weekend, perhaps to give the sponsor the opportunity to relax a little before the Tuesday meeting.  Relax they should because the FDA reviewers appear to have few if any issues regarding the safety or efficacy of the drug.  The questions to the Advisory Committee members from the FDA could not be more basic.  We think this one should get a positive nod from the committee.