Archive for October, 2006

Some lessons from the Plavix patent challenge

October 16, 2006 at 4:27 pm · Filed under Lifecycle, Generics, Legislation

Drug makers continue to battle in Court for the rights to sell (Apotex) or prevent the sale (BMS, Sanofi-Aventis) of a generic version of the blockbuster blood-thinner Plavix.  Meanwhile, the FTC vows to keep fighting the kind of settlement deals BMS and Apotex tried to reach before a group of state Attorneys General gave it the thumbs-down and despite FTC’s highly publicized failure earlier this year to derail a settlement between Schering-Plough and two generics manufacturers.

When faced with such important and potentially confusing matters concerning patent challenges to innovators’ drugs, I turn to my colleague Greg Glass, editor of the Paragraph Four Report and an occasional guest author at Pharma’s Cutting Edge, for the big picture.  Greg hasn’t let us down.  Below he gives us the skinny on the some take-home lessons from the Case That Brought Down a Pharma CEO.   

FJC

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Over the summer, as many of you know, the deal between Apotex and Sanofi-Aventis/Bristol-Myers fell apart, and Apotex launched its generic product.  To label these events as “highly unusual” would be an understatement, and they are so bizarre that I cannot help myself but to discuss them.  While many things have been brought out from under the shadows, it is clear that there is some important information we still do not know, and can these events be applied to pending and future settlements? First, let’s review some key facts from this past summer, some of which the press reported.  Follow me on this as this gets a bit detailed…• On June 26, the U.S. Supreme Court denies the request of the Federal Trade Commission to review the Schering-Plough case, which rejected its position that a brand can’t pay a generic to settle a PIV case, among other things.• The next day, U.S. Senators introduce a bill that would prohibit a Paragraph IV (“PIV”) patent case settlement if the generic company receives anything of value and postpones marketing of its product.

• On July 20, the FTC testifies before Congress about the problems of PIV settlements though it admits that legislating settlement terms (and removing payments to generic companies) would be “challenging.”

• In late July, Attorneys General from several states reject the Plavix settlement.

• On July 27, agents from the federal government raid the office of Peter Dolan, CEO of Bristol-Myers, seeking evidence of anti-competitive behavior in the Plavix deal.

• On July 31, the FTC had yet to approve or reject the settlement, so it expired, allowing Apotex to launch. 

• On August 4, Medco Health Solutions mentions that it expects to get a generic clopidogrel in stock in August.• A few days later, Apotex launches “at-risk” though we later learn that most, if not all of, the risk had been bartered away by BMS as well as its right to file an immediate injunction.  Apotex CEO Barry Sherman reportedly negotiated such terms because he figured the FTC would never accept such a deal.  (One must assume he was gleeful.)

• After the injunction is considered, the Court in New York sides with the brands, mildly suggesting that Apotex may not have that great of a case after all.  However, the Court does not go as far as making Apotex remove product that is on the market.• On September 12, Peter Dolan is removed as CEO; presumably because he did not keep the BMS Board informed of the deal every step of the way and allowed an executive to negotiate, by himself, with Barry Sherman. As you have undoubtedly noticed, the connected dots start with the Schering-Plough case which is seemingly unrelated.  However, I am not a huge believer in coincidences when it comes to politics, and it raises the first question.What is the current FTC position on settlements? It appears that the FTC is still taking the position that any payment to a generic company, along with a “delay” in the launch of a generic product is a per se violation of antitrust law.  It took the same position to Court and lost (see Schering-Plough). Now it appears to be using the legislative process to promote its position.

If the agreement was such a clear violation of antitrust law, why didn’t the FTC reject it? Because it couldn’t, in all good conscience, given the results in Schering-Plough. In this situation, FTC could wait it out, knowing that the deal would expire at the end of July if it didn’t act.

So, why did the settlement fall apart? This is a great question which we may not fully know the answer. Clearly, this appears to be more about politics and money than anything else and appears to have been used to make a point about the broader issue of drug pricing.  The FTC, some states attorneys general, and some senators can now boast (to senior citizens voters) that they are fighting to get less expensive drugs to market.  It is an election year.  The fact that some states rejected the agreement also makes you wonder if their decision was entirely independent of the FTC.Are other settlements at risk for falling apart?  Lately, we have seen many PIV settlements, but these are not likely at risk though there are similarities between these settlements and the Plavix agreement.  Barr Labs had the right idea when it settled Adderall XR® in August by announcing that it would reach the market with a generic before the challenged patent expires. Though this was also true for Plavix, it frames the issue to negate the “generic was delayed” argument.  It may also help to toss in other items like cross licenses and co-promotion deals to make the PIV case a smaller part of a larger transaction.  Remember that how these settlements are portrayed and positioned may be important than what terms they contain.  Frankly, the Plavix settlement terms really weren’t that much different than most others and somehow those other agreements were deemed “okay” while the Plavix settlement was “bad.”So, the FTC is giving up on its position.  Right? Well, not really. During its testimony in front of the Senate, the FTC admitted that it was looking at other settlements which suggests that they might bring the same argument again, in the hopes of winning in a different circuit, thus increasing the odds of the Supreme Court hearing the case as there would then be a conflict in the circuits if the FTC position prevailed.  One would expect it to wait until a case can surface in the 9th Circuit which may be more sympathetic to the broader issue of access to generic medicines.  So, it may not be giving up. Will the Senate bill, dictating terms of settlement agreements, become a law? I don’t know, but I sure hope not. Though the drug industry is highly regulated, last time I checked, the U.S. operated on a sort-of free market system.  One of the last things we need is for elected legislators to be a de facto part of the negotiations between two companies trying to settle a private patent dispute.  If this is fair game, what’s next?

How should a company approach a settlement of a Paragraph IV case?  If you believe the accounts of what happened to Peter Dolan, the safest approach would be to have all executives involved, copy the Board on everything, and never let an executive negotiate alone. Of course, the more people involved, the more likely the chances for a leak of a pending settlement. 

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Connectivity Mapping

October 11, 2006 at 11:27 am · Filed under Technology, Discovery

You’ve likely already read about MIT/Harvard’s project called the connectivity map.  A description of this publicly accessible project was published last week in Science.  The map is a first attempt in the public domain to allow researchers to discover previously unrecognized relationships between perturbants (e.g. small-molecule drugs) and gene-expression signatures on a genome-wide scale.  The Science paper outlines some of the early successes of the approach, one of which–the finding that sirolimus reproduces a gene-expression profile similar to dexamethasone in dex-resistant childhood ALL cells–has immediate and potentially life-saving clinical implications.  The group is proposing that its early successes serve as a clarion call for other groups to join the project to expand its information and thus its utility.

I don’t think this version of a perturbation (connectivity) map, which is a first iteration, is going to impact the state-of-the-art in functional genomic applications at pharma.  Pharma’s own functional genomic “connectivity mapping” efforts are robust enough to make this early version of CMAP little more than a nice addition to a company’s existing arsenal of data.  On the other hand, there is no way that any single company could match or even come close to matching the potential information capacity of an open-source public project like CMAP.  Therefore, industry should support this effort, if not with data contributions, at least with money and with small-molecule drugs for testing, much as it supports the public human SNP map and HapMap projects.  In the future, the CMAP effort should transform itself from an industry nice-to-have into an indespensible tool that will help to accelerate new therapeutic disoveries and simultaneously level the functional-genomics playing field within pharmaceutical discovery.

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Another promising obesity drug bites the dust…but at least we know it. Ruminations on pharmaceutical R&D knowledge transfer.

October 8, 2006 at 9:37 pm · Filed under R&D, Technology, Clinical Research

Nature News story, a well-written example of similar stories to hit the wires this week, highlights the clinical failure of Merck’s NPY antagonist MK-0557, a once-promising treatment for obesity.  The clinical study referenced in the story was published this week in Cell Metabolism (subscription req). 

The usual spin on this MK-0557 story is that this failure marks another in a long line of clinical failures for anti-obesity medications.  Or that for weight-loss drugs to have a good chance of success they’ll have to be tested and used in practice in combinations from the outset.  Yeah, we know.  So, what else is new?

Maybe you’ll read the investment angle–how the clinical failure of MK-0557 is another late-phase failure that Merck can ill-afford, as it tries to re-establish itself as a major to count on for innovation.  Or how about the tried and true–that pharma needs better preclinical models of obesity (not to mention nearly every other chronic disease) if it ever hopes to make major gains over current therapies.

Yawn.

There’s gotta be a more interesting angle to this drug’s failure.  Maybe something along the lines of my recent rant about publishing negative studies and the recently launched Journal of Negative Results in Biomedicine.   

Well, for starters there was the fact that this paper is likely going to be missed by many clinicians who don’t do much basic research, and many that do.  Cell Metabolism isn’t exactly a top-20 clinical research journal.  And this was, after all, an important, 52-week clinical efficacy and safety study that enrolled over 1600 overweight or obese subjects.  But I’m nitpicking.  Those who are interested in obesity drugs will find this article.  And the truth is I don’t know whether Merck wanted the article to pass into publication oblivion or whether Merck actively supported its prompt publication in a journal that the outside authors’ sanctioned.  What’s important is that it was published somewhere, and it was published in a reasonable time frame relative to the actual study conduct. 

Yawn.

There’s gotta be something.  I turned to the literature to check on the clinical-study publications for other investigational drugs in this class.  Not recalling any off the top of my head.  Maybe there’s something important to be said about Pharma’s recent record of publishing investigational drug studies in the peer-reviewed literature?  Now that online clinical-trial data registries are all the rage, are more or less pre-market clinical studies being published in peer-reviewed journals?  That’s an interesting angle, and NPY should make a great test case.  The target (targets actually; there are at least five NPY receptor subtypes and some are found outside the CNS) has been around for a long time.  Many drugs have been synthesized around it (them).  I was just having trouble remembering some of these clinical-study publications, so I turned to PubMed to help my failing memory. 

Neuropeptide Y or its abbreviated version “NPY” turns up nearly 10,000 hits on PubMed (Medline is the primary database for PubMed).  An impressive 1,128 are review articles.  The earliest to refer to the neuropeptide was published in Nature in April, 1982: “Neuropeptide Y–a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide.”  The complete amino acid sequence was published in PNAS later that year (Sept, 1982).  Great, you might think, nearly 25 years since the endogenous peptide was discovered.  Should be tons of clinical studies here.

So, let’s get right to those clinical publications.  Let’s see…limiting the search by publication types ‘clinical trial’ or ‘randomized controlled trial’ yields 116 pubs.  A decent number, but I’ve been fooled by these PubMed delimiters before.  Sometimes they miss stuff.  Using my own, custom, homemade, proprietary, one-of-a-kind, special-order delimiters for clinical studies yields 341 publications [apologies to George Carlin for stealing his bit].

Much better.  If these 341 studies are all obesity treatments targeting NPY that should certainly be enough to examine recent publication trends.  So, I limit further, to articles including the words obesity or overweight.  Uh oh.  I’m down to just 27 articles, and the first two are the Cell Metabolism article and the accompanying editorial, leaving 25.

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