Vivus, Inc. submitted an NDA for Qnexa, a fixed dose combination of phentermine and topiramate for aid in weight management (”weight loss”). Phentermine was approved in 1959 for short-term treatment of obesity. The originator product was discontinued and replaced by numerous generics. Phentermine acts to release norepinephrine which has an appetite-suppressing effect. Topiramate was approved in 1996 for the treatment of epilepsy and approved in 2004 for migraine prophylaxis and hyperammonemia. It is not known what causes topiramine to suppress appetite. According to Vivus, there were over 6 million prescriptions for phentermine and over 9 million prescriptions for topiramate in 2009. Vivus has developed a controlled release capsule formulation containing lower-than-currently-marketed doses (1/8 to 1/2 of phentermine and 1/16 to 1/4 of topiramate). The development rationale was that by combining the two drugs, the doses of each component might be lower than the monotherapy and thus allow for long-term treatment of obesity. Indeed, the combination was shown to be more efficacious than the total weight loss of each component alone.

On July 15 of this year, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met to review the NDA application. The FDA and Vivus briefing information is here. FDA’s position was clear – there was no issue with the efficacy but there were concerns about safety, specifically psychiatric adverse events including suicidality, neurocognitive adverse events, cardiovascular safety (readers may remember the controversy around the anti-obesity drugs fen-phen – an ad hoc prescribing of the combination of fenfluramine and phentermine. Fenfluramine was removed from the market in 1997 due to cardiac valvulopathy), incidence of metabolic acidosis, and teratogenicity. Of these, the FDA appeared to have the most concern about the teratogenicity. Topiramate is a known teratogen in several animal species. The FDA summarized the human evidence:

“Human pregnancy outcomes with topiramate exposure have been tracked in several pregnancy registries including the North American Antiepileptic Pregnancy Registry and UK Epilepsy and Pregnancy Registry. Topiramate monotherapy-exposed pregnancies in the North American registry had a higher prevalence of malformations (4.1%, 95% CI: 1.9, 7.6) compared to controls (1.6%, 95% CI: 1.5, 1.7). The UK registry reported a major congenital malformation rate of 4.8% (95% CI: 1.7, 13.3) from 70 pregnancies exposed to topiramate monotherapy of 200 mg and higher.”

Despite contraceptive counseling and monthly pregnancy checks, 34 pregnancies were experienced on Qnexa clinical studies. Though no malformations were observed in the resulting newborns, the FDA was clearly concerned that Qnexa would be used chronically by pregnant women. Vivus’ briefing information was nearly silent on this issue – maybe they didn’t see it coming? They were well prepared in their commentary at the Advisory Committee meeting. The company consultant, Dr. Gideon Koren, a University of Toronto professor with extensive experience in evaluating the risk of drugs on pregnancy outcomes and founder of Motherisk at the Hospital for Sick Children at the University of Toronto, said that if he counseled a “woman with topiramate — I will reassure her that if she took the drug into pregnancy, she is not likely to have an increased risk for malformations [meeting transcript (PDF), page 80, line 17]. He also argued that the proposed dose of Qnexa is lower and because the women are obese, the dose is “per kilo body weight less than half of what women with typically in epilepsy receive”[ibid, page 79, line 5].

The Committee voted 9 against approval, 7 for approval and no abstentions. During member commentaries on their vote, one member, Dr. Capuzzi said he meant a ‘no’ vote. But several members indicated that their ‘yes’ vote carried with it a proviso that additional studies should be conducted prior to approval. None of the member questioned the efficacy of the product. In fact, most stressed that it was likely to be an outstanding drug to reduce obesity. Rather, they were concerned with safety. In general, they were concerned that anti-obesity drugs would be used for a long time (the clinical trial duration was 1 year, per current Guidance). Dr. Abraham Thomas of Henry Ford seemed to sum up the sentiments of many of the ‘no’ voters as well as some of the concerns of the ‘yes’ voters [ibid., pages:356-7 line 7]

Cardiovascular concerns: “we should start a cardiovascular trial to look at outcomes in a higher risk population before release so we have the data within two to three years of release of the medication. ”

Bone health: “This medication, because of the acidosis, could affect both spectrums of bone health, peak bone mass in the younger generation — because peak bone mass is developed through the mid-20s — and then osteoporosis or fracture risk in the older subjects.”

“We do need more information about suicide risk.”

Dr. Cragan added: “I couldn’t really justify widespread use with the reproductive outcomes concerns that we have. And as I listened to the panel members discuss the other adverse events, it actually raised my level of concern rather than lessening it.” [ibid, page 366, line 17]

Of course, the FDA is not bound by its Advisory Committee votes. Vivus can also submit additional data. The PDUFA date is October 2010.

For fiscal year 2011 (for the U.S. federal government, that means starting October, 2010), the President introduced $38 million in generic user fees in his budget (discussed in this blog). In order to actually obtain this money, Congress has to enact legislation, presumably along the lines of PDUFA. FDA is initiating this process with a public meeting, announced in the Federal Register. The meeting will be held September 17^th at the Hilton Washington in Rockville, MD.

Stakeholders will include the generic industry and the public that depends on generic drugs to bring down the cost of healthcare. Modest fees would allow small companies to continue to participate in this business. Fees of hundreds of thousands of dollars (remember, the 2011 PDUFA fee is $771,000 for a 505(b)(2) NDA based only on Phase 1 data, similar to an ANDA based on a bioequivalence study) could remove some producers from the market. Watch for the large generic companies to push for higher fees and earlier approval times. Approval of generic user fees will add one more reason for industry consolidation. On the other hand, generic user fees would bring important new generics to market faster, potentially reducing the public cost of healthcare.

The legal arguments have been presented well by others (see the FDA Law Blog posting). What I want to discuss herein is whether Lannett can succeed with an NDA; should Lannett have filed an ANDA? The Lannett filing indicates that FDA may be thinking the NDA should have been an ANDA:

I have addressed this situation before in this blog. You cannot have two NDA’s for the same drug product.

This is a situation faced by the many manufacturers of the ’same’ unapproved drugs who wish to gain approval of their products via a 505(b)(2) NDA. The FDA filing of an NDA is not a public record. Unless the sponsor issues a public announcement, the competition will not know an NDA has been filed. Nor will the competition know precisely the content of the filing – the formula of the drug product and the labeling. Thus, submission of an NDA for an unapproved product carries some risk that another manufacturer’s drug product will be approved first. In this case the first approved product becomes the reference listed drug (RLD) in the Orange Book and the other NDA applicants must go through the ANDA procedure.

Sanofi filed its complaint with the U.S. District Court for the District of Columbia.  The suit alleges that the FDA exceeded its authority under Section 505(j) of the Food, Drug and Cosmetic Act (FDCA), and ignored its own precedent regarding approval of generic drugs.  According to Sanofi, the FDA required Momenta to submit additional data demonstrating the safety and effectiveness of its product.  The company claims that the FDA disregarded FDCA Section 505(j)(2)(A), which “specifically precludes FDA from requiring the submission of such [safety and effectiveness] information.”  If the FDA required Momenta to submit such clinical study data, which the FDCA does not require of ANDA applicants, it could be argued that the approval should have been executed under FDCA Section 505(b)(2) rather than 505(j).  A product approved under 505(b)(2) is not bioequivalent to the reference product [my highlight], and is not necessarily AB equivalent.  Thus, it may lose an important market advantage, as the ability to directly substitute a generic product is a key driver of generic adoption.

Readers of this blog should recognize that the highlighted section is wrong. On the contrary, many products approved under 505(b)(2) are bioequivalent to their reference listed product (RLD). These products may also be rated AB. 505(b)(2) may be used to obtain approval for products that not bioequivalent, and some may argue that is the usual case, but a review of the products approved under 505(b)(2) will confirm that most products are bioequivalent to the RLD.

A clinical study is generally Phase 2 or Phase 3, so a 505(b)(2) approved based on a  Phase 1 study is not considered a clinical study and would cost $771,000. 

As always, the first NDA for a small business (less than 500 employees) is free.

Click here for a report on the FDA 2011 Budget and Appropriations.

Office of Generic Drugs (HFD–600)
Center for Drug Evaluation and Research, Food and Drug Administration
Metro Park North VII, 7620 Standish Pl.
Rockville, MD 20855.

This address is also used when mailing IND’s that are used to support ANDA’s.

At Camargo, we advise clients to submit electronic applications whenever possible. We have the software and training needed to accomplish this task. We have set up an document management system that allows each client to securely view all of their documents and to view the eCTD submission at any time.

How do you arrive at the terms? One handy source to learn how to compute the terms was suggested by a friend. The AUTM (The Association of University Technology Managers) has a web page with a manual and an Excel spreadsheet designed for pharmaceutical deals.

DIA Website: FDA Panel Votes To Keep Avandia On Market With More Restrictions (no hyperlink since access is by subscription)

NYTimes: F.D.A. Panel Votes to Restrict Avandia (no hyperlink since access is by subscription)

MSN Website: Avandia Raises Heart Risk But Should Stay on Market, FDA Panel Finds

USAToday: Majority of FDA panel votes to keep Avandia on the market

Yet, the articles under the headlines take very different views. For example, the New York Times followed the headline with “..advisory panel recommended.. Avandia…should either be withdrawn from the market or have sales severely restricted because it increases the risks of heart attacks.”

The USAToday articles starts “…a majority of Food and Drug Administration advisory panel members Wednesday did not recommend taking the diabetes drug Avandia off the market, despite evidence showing it raises heart attack risk”.

Hmmm…, what did the FDA advisory committee actually do? There were a number of questions asked of the 33 members, but a key question on what should be done:

12 – withdraw the product from the market

10 – keep on the market with serious warnings

7 - keep on the market with some warnings

3 - keep on the market with no change

1 – abstain

Clearly, a divided opinion (20 keep in some fashion, 12 withdraw) that appears to mirror the divided opinion presented by the FDA in their briefing materials. FDA’s Margaret Hamburg has indicated that she will be the final decision maker since the review division is divided.

• July 13–14, 2010: Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement 
• Draft Agenda for the July 13-14, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee (PDF - 81KB) 
• Draft Questions for the July 13-14, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee (PDF - 233KB) 
• Pre-Meeting Posting of Slides for the July 13-14, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee 
• Briefing Information for the July 13-14, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee 
• Draft Meeting Roster for the July 13-14, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee (PDF - 105KB) 

• Bupropion acts on the weight control circuit by stimulating the POMC neuron.
• Naltrexone prevents inhibition of POMC neurons by blocking the action of β-endorphin

Bupropion is currently approved for the treatment of major depressive disorder (WELLBUTRIN) and as an aid to smoking cessation (ZYBAN). Naltrexone is indicated for the treatment of alcohol dependence (VIVITROL) and for the blockage of the effects of exogenously administered opioids (REVIA and several generics).

Orexigen states that the company followed the FDA guidance on weight loss products. Accordingly, the company conducted four phase 3 56 week, randomized, double-blind, placebo-controlled trials.  The co-primary endpoints were the proportion of patients achieving at least 5% weight loss and percent change in body weight compared to placebo. According to company presentations, on an intent-to-treat basis, “[a]pproximately 25-33% lost 10% or more of their body weight and 12-16% lost at least 15%”. A summary of the Phase II and IIb and the four Phase 3 trials is here on pages 6-8 (also exploratory trials on smoking cessation and anti-depression in obese depressed patients). Yesterday, at the American Diabetes Association annual meeting, Orexigen presented results of 505 patient/52 site 56-week clinical trial that showed their proposed combination drug product helped diabetes patients lose weight and control their blood sugar better than a placebo.

The NDA was filed March 2010 and accepted for review by FDA on June 1, 2010. Orexigen recently announced that FDA’s Division of Metabolic and Endocrine Drug Products Advisory Committee Meeting is tentatively set for December 7, 2010 to review the NDA.

The weight-loss drug development community is going to learn a lot more about how FDA views this drug category by the end of the year. In addition to the Orexigen product, Vivus’s Qnexa® (phentermine/topiramate CR Capsules) will be reviewed July 15 and Arena’s Lorcaserin (a novel, single agent) is tentatively set for September 16.