Pharma’s Cutting Edge

In December 2006, I described my initial impressions of Google Patent Search beta, a free USPTO patent search engine, powered by Google.  As you’ll read, I wasn’t thrilled with this early release.

So, how has Google fared with some time–nearly 17 months–to marinate its patent search engine?

First off, Google hasn’t promoted the service out of beta yet.  I don’t know how Google decides to promote a new tool to production, but I have to think that many thousands of searches have been made with it since beta testing began, and they’ve had plenty of time to work out the kinks.  Beta schmeta…is it good enough to recommend?

Once again, I’ll compare Google Patent Search directly to the USPTO search engine, as Google has not yet added international patents. 

The Google search interface has been improved and provides simple form field searching for patent number, inventor, assignee, classification code (US and international), issue date, and filing date.  Google’s advanced search operators also work, including the “-” for NOT and “OR”.

The USPTO quick search allows search of all these fields plus some two dozen more, and their advanced search interface allows all of these delimiters to be accessed simultaneously, albeit using a complex syntax.  If you’re doing serious patent research, Google’s search interface will simply not provide you with enough search specificity to meet your needs.

For simple searches, the USPTO quick search and Google Patent advanced search interfaces are similar in user-friendliness and utility.  (The basic Google Patent search has very limited utility.)  So, the key differentiators will be result accuracy and result presentation.

Last time I looked at the Google service, it offered results in a list sorted by relevance-according-to-Google.  In my mind, this made the service virtually useless for industry-based searchers.  Google has since added in a date sorting.  I would have preferred having a patent number sorting option, but date at least makes the search worth doing.

As for relevance, I’m still scratching my head with Google.  It seems to return results in some quasi-random way.  For instance, search the exact phrase (in quotes) “Eli Lilly” the field assignee name, using the entire USPTO issued patent database (quick search) or Google Patent Search (advanced search).  The USPTO returns 3,793 hits dating back to 1971.  Google returns only 527 issued patents dated to 1976, and very strangely, only 461 filings of any status (issued plus applications combined–yes this number is lower than issued patnets alone!), and just 46 patent applications (USPTO returns 94 applications).

Clearly, there is something amiss with Google’s Patent Search.  It really does behave as a beta product, despite its protracted time in use.   It has some potential advantages to the USPTO search in theory, claiming, for example, full-content access to all US issued patents, whereas the USPTO offers full-text access only as far back as 1976.  But it remains fatally flawed for all research purposes except cherry-picking individual patents by number, when you are certain the patent number is correct.

GlaxoSmithKline (GSK) to Acquire Sirtris Pharmaceuticals, a World Leader in “Sirtuin” Research and Development for $720M - FierceBiotech

In what must be the highest valuation paid for a Phase 2 drug and a pipeline of follow-ups (all in the same pharmacological category mind you), GSK is paying nearly three-quarters of a billion dollars for Sirtris. 

That’s $180 million for each of Sirtris’ four years of existence.

Okay, so Sirtris has its share of sirtuin-activator patent applications pending (at least 180, according to the company).  But those aren’t issued patents, are they? 

Three-quarters of a billion.  That’s roughly three-quarters of a billion for each of Sirtris’ one issued U.S. patent.

And they’ve got a small-molecule drug that apparently has cleared Phase 2.  But that leaves another development phase and a regulatory review to go before even getting to market by my math.  

Three-quarters of a billion with at least four more years of development time.

History tells me that pioneering small molecules for diabetes that have cleared this development hurdle have roughly a coin’s toss odds of eventually gaining major marketing approval, and a much lower chance of making it to market and becoming blockbusters.

And yet.

Three-quarters of a billion.  Roughly $9 milion per Sirtris employee.

Are you feeling valued yet?

Symbollon Pharmaceuticals Announces Results of IoGen Phase III Clinical Trial

Normally, I wouldn’t give a company so small in stature space in these pages, but this news release from tiny Symbollon (market cap pre-announcement circa $10M) stirred some memories for me.  You see Iogen, an oral formulation of molecular iodine–Symbollon’s entire pipeline–was also the first drug I was asked to evaluate for possible in-licensing.

That was back in 1998, or maybe 1999.  I remember feeling expertish.

At the time Symbollon was beginning its Phase 2 study of Iogen, but I believe they had some clinical data already in hand too. 

I remember being relatively unimpressed with the efficacy potential but also thinking: “Why not license the thing? It’s probably safe, there’s a chance it works, and it certainly will be cheap.”  Yeah…I was still pretty green then, not fully appreciating the substantial out-of-pocket and opportunity costs associated with any clinical-phase drug acquisition.  Other people more wizened than me realized the true costs, and my employer, also unimpressed with the efficacy data gathered at the time, took a pass.  As apprently did every other pharmaceutical company who saw the package. 

From a glance at the Symbollon website, it looks like the company went it alone for a while and even initiated the pivotal study referenced above by themselves.  Although it appears that they initiated the same study some six months later, after recruiting a license partner in Gardent Pharmaceuticals (nee Bioaccelerate Holdings).  Start a study twice?  Hey, why not?  Give investors their money worth I say.

I have no idea what became of Gardent, but they bailed on Iogen in 2006, leaving Symbollon to go it alone to the bitter end.  Symbollon had initially expected Phase 3 to wrap up in 12 months; it ended up taking nearly 40.  A lack of timely funds and a skeletal management team will do that.  Oh, and they blew through $20 million.  Not much to big pharma, but the opportunity cost would have been several times more.

Pity poor Symbollon, with it’s tiny market cap barely registering a blip and it’s hopes all faded.  My lesson finally complete.

This is a f/u to the piece I wrote in January describing the preliminary (but widely publicized) results from the ENHANCE study of simvastatin and ezetimibe (Zetia) (combination tablet sold as Vytorin by Schering-Plough and Merck) in patients with familial hypercholesterolemia.  The study looked at the effects of the combination versus simvastatin alone on carotid intima-media thickness.  My previous opinions of the study’s meaning aren’t changed with publication of the final results in the NEJM to coincide with the ACC meeting.  In case you were asleep for the past couple of months, ENHANCE was negative for signs of IMT improvement with the combo. 

Expert opinion of the findings has been decidedly negative and prescriptions for ezetimibe (a $5 billion a year drug, counting both Zetia and Vytorin) have tumbled.  Schering-Plough reported that scripts were 3.2 million in January and 2.8 million in February for both drugs combined (a 12.5% drop), while others have reported that Vytorin scripts have fallen 18%.  Several sell-side analysts believe the latest pronouncements from experts at the ACC will further erode sales of Zetia and Vytorin and have cut their sales forecasts and share-price targets for Merck and Schering-Plough.  Given the overreaction to the results thus far, it’s hard to find fault with their reasoning.

I await results from ongoing studies (particularly IMPROVE-IT) with hard CV outcomes as the primary endpoint in a less highly selected population before changing my own use of Zetia.   If ezetimibe doesn’t work to reduce hard CV outcomes despite robust LDL-C reductions, the findings will be strong evidence supporting pleiotropic benefits of statins and arguing against routine use of ezetimibe.  If ezetimibe does work, the utility of CIMT progression in hypercholesterolemia will be dubious. 

Consumers Union Petition

Petition for Better Reporting of Drug Side Effects
I support requiring all drug ads to include a 1-800 number and website so citizens can report drug side effects (petition docket 2008P-0012/CP1).

All too often, drug advertisements fail to present the benefits and risks of using prescription drugs in an accurate and balanced way. It is often the newest drugs that are the most heavily advertised, and it is these drugs whose side effects we know the least about.

The current system for collecting information about side effects catches only a fraction of actual cases. The recent law passed to require print drug ads to provide a 1-800 number and website (FDAAA — P.L. 110-85) is a step in the right direction, but should be extended to include TV ads which are viewed far more frequently and with a greater command of the viewing audience.

Increased reporting of adverse events will help in the earlier detection and better analysis of problems. All television ads should contain information on how patients can report side effects to the FDA.

As you can read above, Consumers Union is trying to improve surveillance of drug safety by promoting patient reporting of “side effects” in drug ads.  A representative of the organization had asked me to blog about the petition, so I am. 

I oppose their effort. Here’s why.

Probably around 1% of adverse reactions to drugs are reported via FDA’s Medwatch system.  Most reports come from healthcare professionals, based on my experience reviewing such reports in the 90’s.  That’s the way it should be, and we need to encourage more of it. 

On the other hand, encouraging more reporting af “side effects” by consumers might actually have its intended effect, which could completely break an already shaky surveillance system. 

Pasive surveillance of reported events can be an effective way of uncovering signals that a drug is associated with rare but potentially serious adverse effects (like hepatic toxicity) or with adverse effects that occur on a background of a common disease (like heart disease) at moderate relative risk (like the risk of heart attack with Vioxx, for instance). 

There are real challenges when interpreting data from such types of surveillance programs.  The most obvious challenge is that there is no concurrent control group for comparison to the drug-treated group (when there is a concurrent control group, we’re speaking of a form of surveillance that is different from the type I’m describing).  A less obvious challenge is separating signal from noise in the data.  Signals are so-called true-positive adverse event reports.  Noise comes from false-positive reports.  Safety surveillance systems strive to maximize signal and minimize noise in order to provide the best possible opportunity for making correct inferences from the data. 

When there is a low percentage of adverse events being reported overall, as in the current environment, the signal is low, and so the detrimental effects of any noise are amplified.  The situation will be improved by encouraging more adverse reports with a high chance of being true-positives and by discouraging reports with a high chance of being false-positives.  How do we do this?

We don’t do it by encouraging patients to fill out Medwatch forms or by calling 800 numbers.  We do it by making it much easier for doctors to capture and transmit adverse events that are possibly or probably related to drugs and by making it much easier for FDA to capture and analyze such reports.  The technology for facilitating such data capture and interchange already exists.  The technology on the doctor end is the electronic medical (health) record (EHR).  Interchange allowing upload of data to FDA can be facilitated using the HL7 data standard known as ICSR.  And on the back end, FDA already uses analytical tools that can make sense of the incoming data.  It is simply a matter of mandating use and providing funds for its implementation. 

Doctors can’t afford EHR for the most part, which is the main reason why its adoption has been so painfully slow.  In an EHR environment, a passive surveillance system can flourish by giving doctors easy, pain-free ways to report anonymized AE reports directly to FDA or other surveillance agencies (like CDC).  It can be as easy as adding a couple of tick boxes and a “send” button to a standard electronic patient encounter form (okay there’s more to it than that, but no so far as end-users can tell).

The US government has not done enough to encourage adoption of this technology, which would really improve drug safety surveillance.  The government should be buying EHR systems and associated training and support for every physician office until the technology achieves saturation.  By becoming the buyer, HHS can mandate that systems be sematically interoperable (be able to talk to each other and to FDA unambiguously).

The cost wouldn’t be as high as you might think.  According to the 2007 US economic census (2002 data), there are roughly 205,000 physician offices in the US.  Some of these offices (let’s say for argument-sake it’s 10%) already have EHR systems, but let’s figure that the government provides support for every office.  Because of discounts from competitive bids, the average cost per office will be much lower than it is today.  Let’s say it’s $50,000 per office on average.  That’s roughly 10.25 billion dollars to outfit, train, and support every physician office in the US with an EHR system and to guarantee that the systems will be interoperable with each other and with FDA.  That’s about what the US is spending each month in Iraq.

That’s what Consumers Union should be pushing for.  Adding to the noise of passive surveillance data will only make a bad situation worse.