The Good, The Bad

The Good

Some interesting news this week about Alzheimers research. First was the news published in Neurology about cutting the risk of dementia with statins. Some physicians believe that the primary benefit of statins derives from their anti-inflammatory properties, rather than, or in addition to, lowering plaque build-up, and this mechanism would go a long way toward explaining the dementia benefit (or so we're told. PB is not a healthcare professional).

Anyway, we're reminded of the benefits that are derived from both widespread use AND disuse of common medications, that are not always recognized until years after their introduction. The mass adoption of classes of medications in a short time period, such as statins have experienced, will inevitably have some kind of public health impact that is not understood or predicted by clinical studies. The negative example is the rate of breast cancer decline following the steep abandonment of Premarin. We may all have lucked out with the statin news, but there are going to be as many negative findings as positive ones, and if pharma is eager to put a new pill in the hands of as many patients as possible in as short a time as possible, they better be prepared to do the public health research necessary to tease out the data to expose the next Vioxx problem.

The other dementia news was the anti-Alzheimers compound that we heard about, helping to detangle the brain. We enjoyed WIRED magazine's take on this. Our first exposure to the story named the drug as Rember, which set off an alarm. Drugs in the pipeline usually don't get a proprietary name until closer to launch, during Phase III trials, so we thought this was some alternative therapy story. But no, there appears to be actual research going on. The compound is about a century old, though. "In the Pipeline" talks about it in depth. And those clever Quakers are going to make it easier for all of us to know when we've got the disease. PB still remembers asking a physician colleague years ago how the diagnosis is confirmed. By cutting open someone's head and examining it after death, was the response.

The bad?

How 'bout them medication error blues?

Lots and lots of them, up 3196% over some time period. More than every other form of accidental death, except for car accidents, COMBINED. Same death rate as homicides. The FDA has replaced riskmaps with REMS but PB's experience with reading these things is that they are generally siloed approaches to medication errors, or they deal only with the possible interaction with some other drug or class. That's all they are supposed to be, dealing with a single compound.

The FDA has published advice to hospitals and the public on how to minimize problems but we'd like to see that backed up by industry marketing muscle. Since the industry recently cut off possible sales and marketing reform legislation with the new PhRMA sales code, how about a similar effort to build a comprehensive technological approach to thwarting medication errors before Chuck Grassley convenes hearings on that issue as well? Don't just worry just about your own meds, worry about how how many people are dying as a whole.

Film fun

The truth is...at the supermarket?
OK, are there any other X-Filers out there who get a little freaked out by this?

Father knows best
A few years ago, Pharmablogger's sister gave us a copy of "Daddy Day Care," and our daughter, bless her heart, made it disappear faster than a dead hooker from Ben Affleck's trailer (hat tip: Kevin Smith).

Last night PB was watching a preview for Juno, when we began to think about our favorite "Dad" movies; films with Dad characters who are actually intelligent, caring, compassionate. So we decided to start a list here, and ask all of our reader to contribute their suggestions. No particular order to these.

1. Juno

Juno's dad says a few biting things to her when she announces her pregnancy, but he's a great supporter and friend to her, who simply didn't see this coming. Favorite line: "Hey there, big puffy version of Junebug!"

2. Fairy Tale

This is a bit of a cheat, because the Dad moment is very brief, coming at the very end, and that's all PB is going to say about it. Because if you have a daughter, you need to see this movie. PB cries at the end every time.

3. Bend It Like Beckham

Dad is played by Anupam Kher, who shows his true colors of affection to his daughter about halfway into the film, sneaking in to watch her play metric football, then finally intervening in the end to allow her to play in the finals, accepting her traveling to America for college, and so on. He's trying to balance holding on to family the traditions of his culture with his daughter's need to grow.

4 & 5. Bride and Prejudice & Pride & Prejudice

The same story, two different interpretations, two great dads. Both of these contain variations of PB's favorite Dad line in literature: Your mother will never speak to you if you don't marry him, and I will never speak to you if you do. What a great show of respect for a daughter, to tell her that she deserves someone who is at least her equal, even if that decision may impoverish the rest of the family. Anupam Kher again in the first film, and Donald Sutherland in the second.

6. Contact

Jodie Foster's Dad is played by David Morse, who learns that his daughter is gifted in math and science, and does a great job inspiring her to excel beyond all of her peers, and think outside the orthodoxy of her field. His influence is so strong that it lasts well after his death when she is a young teenager.

7. Say Anything

Perhaps a controversial choice, since Ione Skye's Dad turns out to be a felon. But John Mahoney's relationship with his teenage daughter still remains something of a model for me. Sure, he puts her on a pedestal, but he's done a great job (another single Dad) encouraging her achievement, and giving her great values, despite his own personal failings. And there's that famous scene where she confesses that she "jumped on" John Cusack, and then expresses relief at her comfort at being able to tell her Dad something like that. Dad holds back his barely veiled concern, because he raised her to be honest, she was, and he knows he has to respect that, or undermine everything he ever told her in the past.

More when PB thinks of some, or you suggest something....

Baseball liner notes

Pharmablogger has noticed a trend toward feminization in sports, and a corresponding complementary trend in the opposite direction. We loved watching our daughter play softball this Spring, we note how baseball teams have worked hard to make ballgames more "family friendly," and we look forward to watching Ryan Howard leading cheers from the bench someday:

"We don't play with Barbie dolls, we just play with bats and balls.
We don't wear no miniskirts, we just wear pants and t-shirts."

We approve, since we would like to see our daughter win an athletic scholarship some day, and be capable of stuffing a field hockey stick up the rectum of any over aggressive suitor should the need arise.

And while PB once purchased a T-shirt at a breast cancer fundraiser that reads "Save Second Base," we must confess that the first time we saw those pink Phillies caps, we thought it must be Carlotta Tendant bobblehead night.

Anyway, we pause here to note some interesting (and dare we speculate, revealing?) quotes in the Inky last Friday. Mike Arbuckle, the Phils general manager, was discussing their latest trade for pitcher Joe Blanton, when he made this point about Blanton's appearance: "We feel his make-up is going to allow him to fit very well in a pennant race. He was attractive for a lot of reasons." I guess this move by the Phillies is just cosmetic.

Immunity?

Since the Supreme Court granted immunity to Medical Device manufacturers in February, there has been heightened discussion about the court taking the next logical step, granting immunity to FDA approved medications, which may occur in the next Court session.

Pharmablogger will devote additional coverage and discussion to this issue in the coming months. For an interesting contrast of media coverage, see July 18th edition of the Philadelphia Inquirer. In the same paper, there was a slightly paranoid sounding article about a meeting in Philly between Pharma execs, attended by a "high ranking official" from the FDA, who was the featured speaker on the topic of immunity. The points about faulty FDA review were spot-on, but PB wanted to specifically call out one sentence: "These corporations will cry that complete immunity pre-emption is necessary because the cost of litigation is suppressing their research and development. That is a lie. " Amen. One of the best-selling pharmaceuticals in the country is an anti-schizophrenia medicine, which has already had one large line extension with bipolar disorder, and the company is seeking approval for an even larger extension with a claim for general anxiety disorder, and major depression. The patient population for this drug could explode even more, with GPs prescribing it. Yet this drug is also a huge litigation magnet for this company already. No matter - full (development) steam ahead.

The second Inky article is about Merck's approval of a settlement sum for Vioxx litigants - $4.5 billion. Now, PB has no journalism experience, and the first article seemed timely based on the meeting that the author discussed. But is it possible that the Inky held the editorial for a short while, knowing that a Merck decision on the settlement funds was imminent? Just wondering.

Overtreated

If I haven't linked to this author, I should have. Shannon Brownlee wrote a good book, and she reiterates some of her arguments in this Washington Post article.

She gets a lot of milage from debunking osteopenia in this article, but as I read her criticism, something struck me as being inconsistant. True, most women with osteopenia will not break a hip, and true, most people with actinic keratoses will not have skin cancer. But my perspective has always been from the side effect world. The statistics that we use to determine a "signal" is similar to the statistics used to predict whether someone will come down with a serious ailment if they have a "pre-disease." So why is one predictive model more valid than another? Well, if you're taking a medication, there's an assumption that its actually doing something positive for you, to make the benefit/risk ration worthwhile. She's right about one thing - there is definitely a growing movement to treat conditions before they even are manifest by using surrogate markers such as low cholesterol or bone density. But don't throw out that surrogate marker philosophy completely. Isn't blood pressure a surrogate marker? Does anybody feel bad just because they have it, or don't they have to wait for the kidney damage first?

From NPR's "Talk of the Nation" - Saline issues?

Wax on, wax off

OK, if Peter Rost can devote unseemly amounts of column inches to Elliot Spitzer, than I'm going to feel free to wax poetical on the heels of our current financial crisis. The following is an excerpt from a poem I wrote a long time ago, called Who Wants to Play? from the perspective of an investment banker:

Our wages come not from the things we create,
but the miniscule squeezings of this or that rate.
I'll earn more than my father by producing much less.
He worked as a craftsman; I'll learn about stress.

The Fed is our lackey; it works toward our ends.
The families we shred, we demand that they mend.
You won't see it coming, then you'll blame the wrong fools.
You can't change a thing when you play by our rules.
We'll crush you beneath our invisible hand
'Cause you cannot resist what you don't understand.

Cheerful, huh? I was in an uncharitable mood at the time. Unlike today! I also wrote an Ode to the Federal Reserve back then. No, really. If you say pretty please, I may even publish it here.

Compare & Contrast

I've been doing some fascinating reading about the admissability of adverse event data in a pharmaceutical product liability case. "Post-sale" duty to warn concerns the marketing experience, and the related spontaneous adverse event reports, and accumulation and analysis of data.

The Third Restatement of Torts specifically addresses post-sale failure to warn duty, and states that the duty arises "when new information is brought to the attention of the seller." There's no affirmative duty to continue to test (forgetting for the moment any Phase IV commitments) but the manufacturer is supposed to keep abreast of scientific literature and related developments.

Now, the Federal Register specifically states that ADRs are not conclusive of causality (21 CFR 314.80(a)). In fact, a company "need not admit, and may deny" causality of an individual report (21 CFR 314.80(k)). The FDA has also stated that “[a]ccumulated [AE] cases may not be used to calculate incidences or estimates of drug risk" in a 1996 report. These tidbits have been used by defendants to exclude expert testimony on the incidence of ADRs, and actual ADR reports themselves, which is a shame for the plaintiffs, because they make such fun reading for a jury. There are exceptions, particularly in a Bendectin case which allowed expert testimony in 1985. ADR reports can be used to prove notice, however. A plaintiff could argue that the mere existence of reports indicates that a company had notice of possible issues, and a clever lawyer would refer to a large volume of reports, hoping a jury would assume that a big stack of 3500A reports meant that the drug had problems, even if they don't get to hear about the content.

Anyway, this is all leading to the Baycol litigation, where the defense for Bayer had evidence about "AER data" excluded from consideration. The decision cited the Federal Register, and those FDA reports warning against using ADR data inappropriately. A quote from an affidavit from Dr Janet Arrowsmith-Lowe, formerly with the FDA and CDC: "It is a well accepted pharmaco-epidemiologic principle that the biases affecting AERs preclude their use in calculating rates of events or in comparing rates of adverse events among pharmaceutical products." The court cited her affidavit several times, and accepted her arguments.

But what if a company chooses to use that type of data in their own defense (click link for "Spontaneous Adverse Event Reporting Information...)? If they make the case that post-marketing reports demonstrate the relative safety of their drug, will they later be able to make the claim to exclude such data in litigation?

Back to the Eighties weekend....

So, have you seen the advertisements for Yaz, the pill that also has indications for PMDD and acne?

If Yaz fails, and the woman gets pregnant, do they sell a morning-after pill called Erasure?

(Hat tip George H.)

The latest screed
New York Times book review of Melody Petersen's "Our Daily Meds."

Day One

at the Health Law Institute was OK. Tomorrow looks more promising.

I had lunch with a woman working for a law firm which has some Big Pharma clients. She posed an interesting question to me, and I responded in kind.

Her client was asking about employees who have licenses as practitioners, who need to log some clinical time to keep their licenses. Some of these nurse practitioners are also sales reps, whose pay is structured on how practitioners in their geographic areas prescribe. What should be done about these nurse practitioners, whose prescriptions could theoretically affect their pay? Would this arrangement violate some kind of anti-kickback statute?

Well, Stark is not a consideration, since they are not physicians. But there may be state regs that mimic Stark, but apply to a wider array of prescribers. An obvious recommendation to the client would be to restructure their pay for the period when they are in the clinic. Fascinating question though. I'd love to know what they eventually do.

I posed a question back to my lunch friend. If a clinical nurse educator is hired to address an interest group like an Alzheimers association, and they are required to discuss only the disease state and not their employer's medication, how might they still violate the Pharma code by inappropriate promotion? Well, the answer may lie in the clinical development strategy the company pursues, through line extensions and sNDA applications.

Did you ever compare labels and indications between two or more drugs in the same therapeutic family, which are fundamentally identical in mode of action. Go ahead - look it up with the statins, for example. PB will wait.

OK, you back? The clinical strategy for these compounds has been geared toward creating something unique in their indications that the other compounds haven't got. So, when nurse educator Betty speaks to a bunch of cardiologists about lipid-lowering strategies, and discusses the need for the patient to reach certain benchmarks in their therapy, wouldn't it be convenient if her company's compound happens to be the only one indicated to reach those benchmarks? She never needs to mention the drug name, as long as she pounds the message about the therapeutic end-points repeatedly. Then the sales reps for the attending docs can follow-up with a visit sometime later.

Free pharmaceuticals for everyone!

Industry executives have banded together to announce a program to distribute health-affirming pharmaceuticals for free for every American. According to a press release from the world's most profitable industry, the program is already in place, and Americans have been benefitting by ingesting drugs that will help to lower their blood pressure and cholesterol, relieve pain, and encourage bodily growth(s). The program is being touted for its low price and convenience. The industry is rolling out the program with no charge to patients, and distributing the medications conveniently through drinking water. "We may consider a way to try to charge patients for this largesse in the future," stated one industry insider, who wished to remain anonymous. "It's outrageous that patients can derive a pharmaceutical benefit like this without any remuneration whatsoever. This makes the Canadian problem seem trivial in comparison."

Legal fun!

Yeah, I do this stuff 'cause I love it.

Pennsylvania Bar Institute's "Health Law Institute," March 11 & 12, Philadelphia Convention Center.

If you're in the mid-Atlantic area, and there are lots of us Pharma people around here, check out this two-day affair next week if you have the chance. PB will be there, and I wish I had posted this earlier to give you a chance to book ahead. Still, its cheaper than most Pharma conferences. The Health Law Institute is not only Pharma topics, or even mostly. But there's plenty to learn about there, and its much more interesting than the last industry conference you went to, I guarantee.

Give me a holler if you will be attending, especially if you're going because I recommended it. Thanks!

Campaign fun!

The Philadelphia Inquirer reports that the race for pharma campaign bucks has now tilted overall to the Democrats. Hillary Clinton leads all comers with $408,000 in contributions, but you won't hear Barack Obama complain too much about that, because he's only about $8000 behind her. John McCain remains as the one candidate who can spout off all he wants about Big Pharma, having collected only $112,000 or so up til now. And spout off he does. Read into the Inky article to get to some of his choicier quotes from the campaign trail. He's up to speed about the Medicaid lawsuits that just returned the first verdict against a pharma company in Alabama and he's no fan of Medicaid Part D, either. He clearly indicates that he wants to introduce more price competition into that program.

Billy Tauzin is quoted, acknowledging the "sea change" in contribution patterns toward the demos, but he doesn't sound phazed by McCain's comments.

Wanna have some fun? Navigate to this page at the Federal Election Commission and type in your company name in the search field. Let's find out if Frank down the hall has made a contribution to anyone! I don't know about you, but my company is always trying to get people to contribute to the company PAC, including inducements like making a contribution to a charity of your choice. It's guaranteed to be voluntary with no retribution, but they've never guaranteed anonymity, because they can't. Give to the company PAC, and your name will appear on this publicly accessible website, same as if you gave to a candidate directly.

John Roberts - Due Diligence foe?

I have a feeling that Chief Justice John Roberts wouldn't care for aspects of my job any more than I do.

When I heard Nina Totenberg quote Justice Roberts on Wednesday evening: "I don't see what more a corporation can do," he said. "What more can the corporation do other than say 'Here is our policies' and try to implement them?" I recognized a kindred spirit.

Why are we hounding our vendors to send us everything they find regarding adverse events, when no other corporation is? Why are we telling our employees to call in every time they hear Aunt Millie complain about her gout worsening, just because she's been taking our blood pressure drug for 10 years?

Because we have no other ideas on how to get any meaningful safety data, and neither does the FDA. We're using these lame methods to pump up our database with nonsense, to show the FDA what good due diligence we pursue. The high-powered epidemiogist brains at our company and FDA can't imagine a requirement for practitioners to report suspected ADRs, or even serious ADRs, or even FATAL ADRs. No, we're going to depend instead on the screening skills of whoever picks up the phone at our rebate fulfillment centers to recognize when a patient is inadvertantly mentioning something negative, however trivial it may be.

And I think John Roberts doesn't care less if we do all this. We've got our policies, and we're generating lots of meaningless data from them. Big deal. I'd like it if John Roberts or somebody else with influence would require us to stop concerning ourselves with every potential petty interaction with patients, and require us instead to practice real science.

M. Butterfly, a review

The current ************ Theatre Company production of M. Butterfly tells an extraordinary and Tony-award winning story, with amazing visual production values. The backdrops are beautiful segmented rings that take on different emotional hues with every sudden change of lighting. Sometimes, too sudden. A little more subtlety might have improved some of the transitions.

But that's the tone of the entire production from the acting perspective as well. The director's notes in the program state that he is no fan of realism and naturalism, scoffing that he can find that just by looking out his window. So his cast attempts no naturalistic acting, with the partial exception of the character Marc, libidinous friend to our protagonist Rene. Butterfly's falsetto makes no attempt to deceive, especially when paired with a rather prominent eyebrow ridge. And the famous five-minute segment where he changes from kimono to business suit and removes his make-up loses the astonishing impact from the original production. This is all by design, and it turns the play into an intellectual discourse on East and West, male and female, reality and fantasy. The audience is not drawn to the characters emotionally. This reviewer felt nothing as the tragedy unfolded, but perhaps I was able to think more about the points brought up during Rene's overlong soliloquy at the conclusion...

-Excuse me, what are you doing?

I'm writing a review. I went to see a play this evening.

-What does any of this have to do with pharma?

Well, nothing I suppose. I just felt like writing, raising a few points I was thinking about...

-But this isn't the place! Leave your intellectual masturbation at the door.

Screw you, its my blog. I can write whatever I want.

-Not if you want people to read it.

This is psychotic. Who the hell are you?

-How about if I guess what you are. A frustrated pharma employee, a wannabe something else, a jerk with a script half-finished on his flash drive...

Screenplay, thanks. So what?

-Oh, wants to be a movie writer? Lemme guess, the story of your pathetic life, made profound somehow. Maybe you can scab during the strike. Who do you have playing you?

Edward Norton, asshole. (Flips through the playbill) Anyway, look here at the benefactor list. GlaxoSmithKline, Shire, Johnson & Johnson...

-Tenuous my friend. Your point?

Well, maybe I don't have one. Or just that pharma money goes everywhere, supports everything.

-We know that already. But Arts are good.

Yeah, I agree. I mean, I actually paid for these tickets, but we've got VPs on boards of various theatre companies, regional symphonies and so on. I've gotten all kinds of free tickets over the years.

-Stadium boxes?

Yeah, but they're harder to come by. At least for me. The sales and marketing guys use them.

-So, whore you've been, whore you'll be again?

I'm not sure if I'm the whore or the pimp. Or which is worse.

-Sounds like you have no self-respect.

Probably not. Neither does a business willing to pony up $650 million in fines, and claim it was just due to a difference in interpretation of Medicaid rules. Totally innocent, of course.

-Yep.
-So how do we end this?

One fine day...no longer to live with dishonor.

-Let's not do anything hasty....

No. Its too late for haste. Good night, my butterfly.

A question for my new friends

A vendor stopped by the other day, and we had an interesting chat about what they are doing for my company, and any legal issues that might pertain.

You see, they're performing social media monitoring for us, for a number of our products, and for our corporate image in general. They're checking out a number of blogs, using technorati and other blog rating tools (I forgot to ask about blogshares! Pick up your shares of pharmablogger today! Cheap!). They're following product discussions on cancer and psychiatry related patient websites. And they're giving us reports on everything they read.

I thought about one of our products in particular that has two key characteristics that interest me. First, it the subject of massive litigation, and second, it has a large amount of sales for off-label uses. Now, I've previously invoked the Divine Wow in these pages, asking that he guide our sales force to be not advising docs about these off-label uses. So for the moment, let's assume my prayers have been heeded, and we won't be on the wrong end of another Neurontin suit.

Yet our product teams are receiving reports about all of the off-label use of our drug from these vendors, as well as reading accounts such as this Wall Street Journal article about dementia patients, accompanied by warnings from the FDA like this. We also know that we're selling outsize amounts of low-dose tabs of our drug, that would not amount to therapeutic doses for its intended purpose, but are enough for the common off-label use. And then there's the IMS Health data. In short our sales force know what's going on out there.

So with all this knowledge about our product and how it's being used in the real world, how protected are we by simply claiming, however accurately, that we're not actually promoting the off-label use? Or in other words, does all of this awareness impose any duty on us to act, to warn, to advise doctors not to use our product inappropriately?

I posed the question to the vendor, and asked if they are providing any legal advice with their website content reports. That's not their function, it turns out. It should probably be mine, but I'm too tired to do the Lexis search tonight.

Even if I didn't find anything, just imagine the jury impact of the facts above. Our company is raking in billions of sales from a product that has a huge percentage of off-label use, that is inappropriate and harmful and maybe even fatal according to the FDA, and we're very aware that this is taking place, even if we're not instigating it, and we're not doing anything to stop it. How would you rule?

I might also add that we are not the only ones researching ourselves on the net. The plaintiff firms and "natural products" companies are doing it as well, but at least we're not actually posting or steering discussions in the patient forums (fora?). Heartening to know we're at least a half-step more ethical than law firms, isn't it? And of course, all-natural products never harmed anyone, right Socrates?