Posts tagged ‘Advisory Committee’

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.

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? 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 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.

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.

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.

Seattle Genetics – An Up and Down Week

Seattle Genetics had an up and down week last week.  The FDA’s Advisory Committee gave a positive recommendation for the company’s Hodgekins lymphoma drug ADCETRIS (brentuximasb) yet the stock went down.  The Seattle Genetics Chairman is quoted as saying he is still positive about the drug.  We tend to agree with him.  Some of the press has been questioning the approvability of the drug because there are only two small studies in support of the application.

There are several things that are very much on the positive side for Seattle Genetics on this.  The first is the indication – refractory Hodgekins lymphoma, refractory being the operative word here.  The second thing is the data.  Yes, the definitive trial presented is a Phase 2 single arm study with only 102 patients but the results were outstanding, clearly much better response rates than literature results for other treatments that have been tried in these patients.  The third thing appears to be the dialog that the company has been having with the FDA during the course of the development of this drug.  In the Briefing Document for last weeks Advisory Committee, the FDA seems to imply that the company has met all of the agreements they made with the FDA to get to this point.  The final point is also a reference the FDA makes in the Briefing Document to the February 2011 meeting of the Advisory Committee in which the criteria for acceptability of a single arm study were discussed.  Seattle Genetics seems to have met the criteria discussed and agreed to during that AdComm meeting.  So, the only thing standing in the way of approval is company agreement and FDA acceptability of the necessary confirmatory trial.

We think it is likely that Seattle Genetics will continue to listen to and agree with the FDA, particularly with regard to the design of the confirmatory trial.  That being the case, FDA seems inclined to approve the drug.

EYLEA PDUFA Date opinion

Regeneron (REGN) is probably still basking in glory of their recent unanimous recommendation from the Advisory Committee for EYLEA (aflibercept opthalmic solution) Opthalmic Solution for the treatment of age related macular degeneration.  The company should now be directing its focus on the upcoming PDUFA Date of Aug 20, 2011 and anticipating an approval.

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.

SUTENT (sunitinib) Advisory Committee Meeting

On Tuesday, April 12, 2011 the FDA Oncology Advisory Committee will discuss Pfizer‘s application for the use of SUTENT in patients with unresectable pancreatic neuroendocrine tumors.  SUTENT has 2 approved indications, including use in patients with advanced renal cell carcinoma.

Based on the issues raised in the FDA Briefing Document, Pfizer might want to spend some time explaining their regulatory/development strategy.  Specifically, the FDA seems to have challenged the company’s choice of a single Phase 3 study using Progression Free Survival as the end point instead of Overall Survival, especially since Pfizer chose not to avail themselves of an End of Phase 2 meeting with the FDA.  It doesn’t appear that Pfizer got FDA agreement through an SPA either.

The Advisory Committee will probably focus on the conduct of the study though and the role the DMC had in the decision making process other than safety.  The major issue seems to be the halting of the trail with only 28% of the subjects enrolled and the predictive value of this limited number of PFS patients from a single study.

One study with limited enrollment, PFS instead of OS – I think the discussion will be short and predictable.  The recommendation will be negative.


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.