Light blogging today…as other commitments are banging on the door, however, in relation to a couple of readers comments, I need to say a little more following up on my post on The Lancet vs Crestor issue.

Public Citizen is the most active consumer rights organization in healthcare in the US and Sidney Wolfe and his team have a consistent pattern of identifying problem areas. Public Citizen has a somewhat splotchy record in calling what’s harmful or not in medical care.  It was the driver behind getting silicone breast implants banned, while my reading of the medical evidence is that they weren’t statistically harmful.  However, they often are right and they recently put out a "do not take" advisory on Crestor in their Worst Pills Best Pills newsletter. Their logic was that in the clinical trials Crestor had caused cases of rhabdomyolysis in patients on 80mg doses–this is of course the disease that Baycol caused, even though Baycol never had those results in its clinical trials.  Astra-Zeneca subsequently  lowered the dosage of Crestor available, but I’ve heard an unconfirmed story of two cases of rhabdomyolysis recently appearing among Crestor users. Both cases were outside the U.S. and one patient was using the 40mg dose, the other was being uptitrated from 20mg to 40mg. In other words  very bad side effects may be occurring in smaller doses than were seen as causing rhabdomyolysis in the clinical trials. The Lancet specifically mentioned this risk in its editorial.

I’m in the scientific caboose as regards knowing about whether any of these statin issues are true or not.  My point is not that statins are harmful. While it’s very unlikely that Crestor, Lipitor or Zocor will be pulled from the market, people in the health care mainstream need to realize both that it could happen (and the Lancet article may be a "signal event" in that process) and that the impact of such an event would be huge on the pharma market.

I’m going to start this with a little personal info. I am an ideal candidte for a life-time regimen of statins. I’m 40 years old. I have high-ish cholesterol and have had for a while, and my father had a  life-saving quadruple by-pass when he was 64. I do exercise but I’m careless about my eating habits and actually I’m sitting here eating a mid-afternoon snack of potato chips. (Incidentally, the chips are Safeway’s own brand Barbecue flavor, the best since the very evil Frito-Lay bought and closed Eagle Chips, whose Mesquite Thins BBQ were so good they must have been laced with crack cocaine. Where the hell was the Anti-trust guy at the DOJ when that happened? But I digress….).

As you know, statins lower "bad" cholesterol (LDL) and hence reduce heart disease.  There’s not too much dispute about that.  There’s also not too much dispute about the fact that they are financially the most important class of prescription drugs in the pharma marketplace and, as I posted about here, their future can make or break huge companies. Baycol’s removal from the market nearly broke Bayer, and Lipitor’s current success is responsible or keeping Pfizer top of the heap. Hence there’s an enormous amount riding on statins, and it’s a classic case of spend now, recoup later. For instance, after taking them for 25 years an at-risk 40 year old may avoid heart disease.

There are, though, repercussions from taking statins.  The side effects from Baycol included killing enough patients due to the kidney disease it created that it was withdrawn from the market.  A rational economist might say that the deaths of 52 patients were worth the millions Baycol would save from heart disease, but that’s not how humans work.  We like seeing the "identified life" (or conversely don’t like seeing the "identified death") and we don’t care too much about the unidentified lives that might be saved in years to come.  And of course in the case of Baycol there were alternative statins like Lipitor on the market. Lawyers who have already won over $500m with more to come from Baycol’s maker Bayer, are closely monitoring this situation! Here was a list from some class-action lawyers of various side-effects of Baycol, put above those the same lawyers claim are related to Lipitor.

Baycol’s alleged Side effects                           
>  Fibromyalgia                                                
>  Kidney Failure                                              
>  Memory Loss                                                
>  Myositis (muscle pain)                                 
>  Rhabdomyolysis  (leads to kidney failure)    
>  Hip Joint Problems
>  Nausea
>  Kidney & Urinary Tract Disorders
>  Liver Problems

Lipitor’s alleged Side effects
>  Fibromyalgia
>  Kidney Failure
>  Memory Loss
>  Myositis (muscle pain)
>  Rhabdomyolysis  (leads to kidney failure)

By now you’ll see where this is going.  If only a very few people have fatal complications from any drug, the trial lawyers will jump all over the pharma companies.  Of course the pharma’s fight very strongly to protect their turf and they are only really vulnerable when they "agree" with the FDA to withdraw a drug from the marketplace; something that has happened with increasing frequency in the past decade.  However, the sheer size of the statin market is so huge that it attracts pharma cos and trial-lawyers like moths to a lamp.

Last weekend, though, something new entered the picture. The world’s oldest and one of its most respected medical journals The Lancet came right out and said that a new statin, Crestor from Astra-Zeneca, had been rushed onto the market by the company and that the company had effectively pressured the FDA and authorities in other countries in the approval process.  For details go read The Lancet’s editorial and the accompanying rebuttal from the CEO of A-Z, Tom McKillop. The science of the issue is well covered by bloggers like Derick Lowe at In The Pipeline, and the impact on medical practice and how treatment patterns actually get adopted are well covered by the renaissance-doc Medpundit. But before you go look at their articles, let me end my market analysis and then my personal story.

Analysis: The Lancet says, while statins work to reduce LDL, we have enough of them about already. Meanwhile it says that Crestor–for which it criticizes the legitimacy of some of the clinical trials–reduces LDL but hasn’t yet been proven to reduce heart disease. As such it is being rushed to market for the primacy of A-Z’s profits. (I’ll refrain from going "Duh!). To my recollection only Pravachol (or is it  Mevacor?) which has been around for years, has had the time for a follow-up and can thus boast that it reduces heart disease and associated mortality as a consequence of lowering LDL.  It may well be that Lipitor, Zocor, etc and Crestor do, but as McKillop points out, they haven’t had time to prove themselves in that end-point, though they are all rushing through the clinical trials trying to prove so. The real development here is that a respected journal has cried foul on the whole pharma company process of getting a drug onto the market as quickly as possible. And they’ve directly linked that process to the withdrawal of Baycol due to its (fatal) side-effects. The ubiquity of those side-effects versus the positive saving of lives many years into the future is the key to the future use of statins. If physicians are essentially pushing statins onto patients based on "incomplete" clinical trials slanted towards a particular drug, the Lancet is right to raise a warning flag. Plus it will inevitably encourage other stories of side-effects, lawsuits and possibly reforms in how the FDA conducts approvals. However, don’t forget that the side-effects might be very, very rare, and so drugs that are good for the vast majority of people may be taken off the market. Watch this space very carefully.

My personal analysis I actually talked to my doctor about this a week or so ago. I asked about his view on statins without mentioning my fear of side-effects. Tacitly acknowledging my concern about doing something now with a potential near-term cost for an uncertain long term pay-off, he told me to think again when I’m 45.  Perhaps my early 60s and the threat of heart disease will seem closer then.  There’ll certainly be a ton more research for me to look at to assess the long-term use of these new statins.  Plus as an added bonus, if they’re off patent, they’ll be a darn site cheaper too!

Merck, which span off Medco as featured in the previous story on today’s THCB, has not been having such a good time as its former subsidiary. It’s recent lay-offs of over 4,000 has lead to the now quite widespread belief in New Jersey that the sky is falling.  For instance this Reuters’ article says that the pharmaceutical area (is) no longer (a) safe haven for jobs.  It raises all the issues that THBC readers will be familiar with–Canadian imports, drying pipelines, Medicare drug coverage, expiring patents, government probes, generic competition, and more.

Perhaps it’s time for a little perspective here. No question that pharma is in a tight spot compared to the cream and jelly days of the late 1990s. However, this industry has always been tremedously profitable.  Some of my former colleagues some time ago went to see a company that’s now part of a giant UK conglomerate (the corporate name has expired but think of a common greeting). They toured the research facility and were amazed at the plushness, the marble sinks and the general over-abundance.  Their host noticed their observations and after noting that the policy consulting guys were always telling them to not be out in front with their profitability, said "we had to hide the money somewhere!" Even if big pharma’s profits fell by half, it would still be the most profitable business in America!

The last time the stock market beat down the Pharma stocks was in 1994.  If you’d bought Merck stock then at between $14 and $18, you’d still be very happy now.

While I was (very worthily) working out at the gym last night I noticed that November’s Smart Money had an article on Lipitor. Given that Lipitor is the single biggest product in health care, currently at $8 billion in revenue, it caught my eye. So I stuck in the reading tray on the elyptical trainer and read away as I elypted. The article (not available on-line) basically said that in a number of cases Lipitor has caused extreme muscle pain and (more devastatingly) alzheimers’ type memory loss in several patients. The article suggested that high doses (above 20mg of Lipitor) actually have the equivalent of 40mg of Zocor, one of its major rivals, yet Zocor can also be obtained in much lower doses (5mg and 10mg) which have virtually the same effect in lowering cholesterol.  Why doesn’t Pfiizer make Lipitor in lower doses?  Bob Erlich, now an industry consultant  running DTCPerspectives Magazine but the guy responsible for Lipitor’s launch at Parke-Davis is quoted as saying essentially (I’m paraphrasing here) that one dose made it easier for the physicians to prescribe as they didn’t have to bother matching patient and dosage.

The article goes on to suggest that independent (i.e. non-pharma funded researchers) have established the high dose to muscle pain link and that the memory loss issue is well known. Behind this is a strong hint that Pfizer is too big to fight either in the dissemination of the message to doctors, or in the law courts–apparently no lawyer will sue until the FDA has withdrawn the drug from the market.  Pfizer for its part acknowledges that the muscle pain is a recognized side effect, but claims that the memory loss–which the article focuses on as it’s pretty devastating–has nothing to do with Lipitor. However, everyone remembers that another statin Baycol was on the market until it was found that in a few cases it caused severe liver damage and was recalled.

It doesn’t take long googling to find several dissatisfied Lipitor users with intense muscle pain and others with transient or long-term memory loss. Unfortunately the Smart Money article doesn’t give any denominators, so there’s no real evidence other than these anecdotal stories about whether significant numbers of people have had these reactions to Lipitor.  So despite the heart-rending stories, you can’t draw any conclusions. Also don’t forget that in the grander scheme of things (if you believe the conventional wisdom that lower cholesterol reduces heart disease), Lipitor is saving thousands of lives for each one it hurts–if it does hurt. This argument is played out in this article on theheart.org (long registration process required.)

From a business perspective what’s important here is the perception of risk.  If statins work for millions and millions of people but a few people allegedly suffer from its side-effects, that’s really the same story that existed for Baycol.  The FDA has been criticized for allowing too many drugs on the market that have to be withdrawn.  Almost always the reason for the withdrawal is a nasty side-effect (e.g. death!) for a very small minority of patients. For Pfizer and its $8 billion drug, there is a very low but existing risk that this could be the end result for Lipitor. Pfizer’s stock has been off slightly in recent months on fears that some patent lawsuits might hurt Lipitor and Zoloft.  Of course that’s nothing to what would happen if Lipitor had to be withdrawn, so watch this wildcard.

From THCB’s legal office, Matt Quinn is back on the track of health care fraud once again.  This time he’s turned his attention from Medi-Cal to big pharma:

The new edition of "Fortune" (the one with, as I remember, Andy Fastow in handcuffs on the cover) also has a great article about the efforts of the Michael Sullivan and his US Attorney’s office in Boston to crack down on fraud by the pharmaceutical industry (only first part avail free).  In a speech at this year’s Pharmaceutical Marketing Congress in Philly that, I’m sure, went over like a fart in church, Michael Loucks (who runs the health care Fraud unit in Sullivan’s office) lectured the assembled industry leaders:

"Since 2000…drugmakers (have) coughed up more than $2.2 billion to settle such civil and criminal violations as kickbacks to doctors, overcharging, and marketing drugs for unapproved uses…No other sector of the health-care industry," he said, "has ever paid similar amounts in health-care fraud investigations in so short a time."

While some suspect that Sullivan has higher political ambitions and is simply attacking big pharma because it’s an easy target with deep pockets, the US Attorney’s office states that its main concern is "that drug companies are corrupting medical judgment by paying off doctors, then passing on those costs to consumers."  Strict oversight, he argues is "pro business."  That whistleblowers get a cut of the judgment doesn’t hurt either.

According to the article, in 2002 the average American incurred $5,037 in medical costs.  By 2010 that number is expected to jump 60% to $8,368.  As much as 10% of that pricetag, the article postulates, is fraud.

With a trend (see this article in AIShealth’s Government News) of reinvesting money from Medicare and Medicaid fraud back into healthcare, wouldn’t a great use for this money be to invest in 1) beefed up investigation and oversight efforts and 2)  a task force to simplify and streamline Medicare’s rules?  While this would ultimately (hopefully!) be a self diminishing revenue stream, it would serve the good of the taxpayer by driving efficiency in the healthcare system as a whole while focusing enforcement efforts on those who intend to defraud vs. those  who are simply confused with the rules.  And best of all it would be totally self funding (with, perhaps, a little left over for investment back into the provision of care).

All that you need to know is in today’s Harris Poll. 77% of Americans think that it’s unreasonable for pharma companies to try to make it impossible for American consumers to buy drugs from Canadian pharmacies over the Internet. Yet only 7% of Americans have done so.

If I was running a public policy group at PhRMA I’d be thinking of ways to try to beat a graceful retreat here. After all, do you think President Dean’s FDA will be quite as helpful as the current one? Better to have Canadian prices on imports rather than get this far enough up the American political consciousness that we end up with Canadian-style pricing here.

Forbes is pumping out a lot of interesting articles on the pharma market these days.  In an article called The Diagnosis For Medical Diagnostics they raise the issue of pairing diagnostics with drugs.  The basic problem is that as drug development becomes more specialized, genetic-based diagnostic testing pinpoints who the drugs will work for.  So the drugs will be more likely to work in those patients and have better results. This is a good thing! 

However, if we know who the drugs will work for, we’ll also know that the same drug won’t work so well for other patients. It’s likely therefore that newer drugs will only work for a smaller share of patients with any particular condition. For the drug to be profitable either the it must cost more per patient or less to develop.  The CEO of Genta quoted in the article doesn’t believe that the cost of drug development–the $800m in the title–is going to come down, which means that their drugs (and presumably many others) are going to cost significantly more per patient than currently available less effective drugs.  And as Jane Sarasohn Kahn mentioned in this recent post, "It’s not clear really who will be willing to pay for innovation". Given that patients are gong to want these new drugs, this leaves both the pharma cos and the rest of us with a big problem–particularly if Medicare is going to pay for drugs (uncertain, but likely) and seniors are going to vote (damn certain!).

Health care expert and all-round wonderful person Jane Sarasohn-Kahn of Think-Health has some added thoughts about what’s likely to be happening inside the pharma industry to deal with the "pipeline problem" discussed in this recent post. Jane suggests you keep your eye on three related developments:

1.  A lot more co-marketing agreements between pharmas (a la Bayer and GSK’s venture into Levitra, Viagra’s competitor for the moment)


2.  Pharmas are looking to biotech for new formulations, but they’re also looking to smaller pharmas too for licensing deals.  This will be important over the next few years.  Obviously, biotech will be important in the longer term, but the juries are still out on so many very expensive drugs. We will be hitting the wall on who is going to pay for those expensive bio drugs, and I anticipate that will be a big area of contention.  It’s not clear really who will be willing to pay for innovation.

3.  We can’t switch too many more drugs to OTC as allergy and GI were the low hanging fruit here.  We’ll get a bit more savings out of switches, but then you get into another category of drugs that really does require professional input — depression/mental health, migraine, anti-infectives (gotta watch out for resistance there and over-indulging the paeds population whose mothers aren’t patient enough when it comes to ‘watchful waiting’ over ear infections), cancer, HIV/AIDS, etc.

There’s been substantial worry in the pharma business about the future of the pipeline–and rightfully so.  More than any other business, pharma companies tend to rely on one huge hit, and the spin-offs from it, rather than a steady stream of new products. The recent round of consolidation in which Glaxo and Pfizer got much, much bigger was in part an attempt to diversify their portfolios by acquiring other blockbusters, and also an attempt to make the overall corporation less vulnerable to the patent expiry of others.  As I wrote about a while back, the specter of Claritin’s disappearance removing billions in revenue off Schering Plough’s income statement haunts all pharma CEOs’ nightmares.

So how does the potential pipeline look for the latter part of this decade, when many of today’s blockbusters come off patent? Well according to a Datamonitor study quoted in this Forbes article, Pfizer has 5 potential biggies with a guestimated revenue of up to $5 billion in 2008.  GlaxoSmithKline (GSK) has only one with estimated revenues of only $700 million. Pfizer’s 2001 sales in the US were $17 billion, whereas GSK’s were $15 billion.  So it appears that GSK is more likely to be doing what it can to find more ways to fill its pipeline. Expect more activity in both big pharma M&A and looking to biotech to fill the pipelines from the big players in the next year or so.

For a good general report on the pharma industry from (believe it or not) the CMS, click here.