Remember the media assault on Eli Lilly for suspending it's study of prasugrel last year, assuming malfeasance, substandard results, etc? Let's roll the tape from Matt Herper's dark commentary entitled "Lilly's Scary Silence":

"It's hard to see how that could be any comfort to investors. As is often true, there is a big downside risk to investors ahead of the data release on Nov. 4. But investors should be equally concerned about whether or not Lilly is giving straight answers about its data. If these studies do bode badly for prasugrel, investors have a right to know now. If they don't, Lilly still needs to give a clearer explanation. If the company can't do that, the safest thing is probably to assume the worst and sell the stock."

http://www.forbes.com/sciencesandmedicine/2007/10/25/pharmacuticals-prasugrel-lilly-biz-sci-cx_mh_1026lilly1.html?boxes=relstories

Science doesn't just snap to the whims of investors and reporters...but in case anyone cares here's an update from http://www.fiercebiotech.com




Study Results Show Investigational Drug, Prasugrel, Cuts Risk of Stent-Related Clots by More than Half Versus Clopidogrel
March 29, 2008

Reductions seen as soon as three days and out to 450 days in patients who received either bare metal or drug-eluting stents
CHICAGO, March 29, 2008 /PRNewswire-FirstCall via COMTEX News Network/ -- The investigational antiplatelet drug prasugrel plus aspirin produced a marked and highly statistically significant reduction in the risk of coronary stent thrombosis (ST) - a major concern for physicians and patients with potentially fatal consequences - in patients who received a stent as compared to standard therapy with clopidogrel (Plavix®) plus aspirin (1.13 percent vs. 2.35 percent, p<0.0001), according to a stent analysis from the head-to-head TRITON-TIMI 38 trial.

The findings were presented today by Dr. Stephen Wiviott, an assistant professor of medicine at Harvard Medical School and investigator with the Thrombolysis in Myocardial Infarction (TIMI) Study Group, at the Society for Cardiovascular Angiography and Interventions Scientific Sessions with the American College of Cardiology's Innovation in Intervention: i2 Summit, in Chicago. In addition, the manuscript was simultaneously published online by the British medical journal, The Lancet.

In the TRITON-TIMI 38 trial, whose overall results were previously published, 12,844 of the 13,608 enrolled patients received at least one intracoronary stent. Of those patients, 6,461 received a bare metal stent (BMS), 5,743 patients received a drug-eluting stent (DES), and 640 patients received both BMS and DES at the time of enrollment. Stent thrombosis was a pre-defined secondary endpoint in the trial.

Prasugrel reduced the relative risk of coronary stent thrombosis (a new clot at the implanted stent site) over clopidogrel by 52 percent (1.13 percent vs. 2.35 percent, p<0.0001). In patients who received drug-eluting stents (DES), treatment with prasugrel reduced relative risk by 64 percent over clopidogrel (0.84 percent vs. 2.31 percent, p<0.0001), and by 48 percent in patients who received bare metal stents (BMS) (1.27 percent vs. 2.41 percent, p=0.0009).

In the analysis, prasugrel was consistent in reducing stent thrombosis, compared to clopidogrel, whether assessment occurred early or late (<30 days and greater than or equal to 30 days, out to 450 days, the median duration of therapy), regardless of the type of stent used (bare metal or drug-eluting), and regardless of which academic research consortium (ARC) definition of stent thrombosis was used - definite/confirmed stent thrombosis, definite/confirmed plus probable stent thrombosis, and definite/confirmed plus probable plus possible stent thrombosis. Definite/probable stent thrombosis was reduced by 59 percent in prasugrel-treated patients within 30 days of stent placement (0.64 percent vs. 1.56 percent, p<0.0001), and by 40 percent after 30 days (out to 450 days, 0.49 percent vs. 0.82 percent, p=0.03).

"Stent thrombosis is very serious, given the high risk of mortality. In TRITON, among 210 patients with definite or probable stent thrombosis, 186 (89 percent) either died or experienced an MI as a result of the event," said Francis Plat, M.D., vice president, clinical development, Daiichi Sankyo Company, Limited. "We were excited by the results of this study and the possibility that prasugrel may someday provide an alternative treatment for ACS patients undergoing PCI and receiving coronary stents."

A 19 percent reduction in risk was observed with prasugrel compared with clopidogrel among all patients receiving a stent (9.7 percent vs. 11.9 percent, p=0.0001) in TRITON's primary endpoint of cardiovascular death, non- fatal heart attack, or non-fatal stroke. A 20 percent relative reduction favoring prasugrel was observed in the primary endpoint in patients who received only a bare metal stent (10.0 percent vs. 12.2 percent, p=0.003), and in patients who received only a drug-eluting stent, results showed an 18 percent relative reduction in the primary endpoint favoring prasugrel (9.0 percent vs. 11.1 percent, p=0.019). Fatal stent thrombosis occurred in 18 (0.28 percent) patients treated with prasugrel and 29 (0.46 percent) patients treated with clopidogrel (p=0.10). Of note, of the 210 patients with stent thrombosis, 89 percent either died or had a myocardial infarction associated with the event.

The rate of major bleeding was higher in all patients receiving a stent treated with prasugrel vs. clopidogrel (2.4 percent vs. 1.9 percent, p=0.06). Major bleeding in both DES and BMS prasugrel-treated groups when compared to clopidogrel-treated patients was 3 percent vs. 2 percent (p=0.34 DES) and 2 percent vs. 2 percent (p=0.09 BMS).

In addition to a reduction in the primary endpoint (CV death, non-fatal heart attack, or non-fatal stroke), a significantly lower rate of the composite endpoint of cardiovascular death, heart attack or urgent target vessel revascularization (UTVR) was observed with prasugrel vs. clopidogrel for both bare metal stents (10 percent vs. 12 percent, p=0.009) and for drug- eluting stents (9 percent vs. 11 percent, p=0.004). A significant reduction was also seen in heart attack alone (8 percent vs. 10 percent, p=0.003, BMS and 7 percent vs. 9 percent, p=.006, DES). In DES-implanted patients, regardless of those receiving only sirolimus-eluting or paclitaxel-eluting stents, there was a similar magnitude of event reduction with prasugrel compared to clopidogrel.

For the entire cohort, sub-acute stent thrombosis (24 hours to 30 days) was 0.36 percent in prasugrel-treated patients vs. 1.19 percent in clopidogrel-treated patients (p<0.0001). DES-implanted patients had lower rates of stent thrombosis compared to BMS-implanted patients, and prasugrel was shown to significantly reduce stent thrombosis in DES-implanted patients within the first three days compared to clopidogrel (0.14 percent vs. 0.63 percent, p=0.003) as well as for thromboses that occurred >30 days following the DES implantation (0.42 percent vs. 0.91 percent, p=0.04).

"The reduction in risk seen in patients in this analysis treated with prasugrel over patients treated with clopidogrel is encouraging for high-risk patients with acute coronary syndrome being managed with PCI," said J. Anthony Ware, M.D., Lilly vice president for cardiovascular/acute care.

It would great if, just once, coverage about clinical trials focused on the unpredictability of science and the inherent difficulty of designing "real world" studies of the effect of drugs that produce desired results, particularly a measurable reversal in biochemistry that contributes to death.

That will not happen with Vytorin, except in the breach. To be sure the original:" these findings plus future biologic and clinical evidence could confirm that the benefits of lowering LDL cholesterol may depend not only on "how low you go" but also on "how you get there."
http://content.nejm.org/cgi/content/full/NEJMe0801608


This is a point that Eric Topol has been making since the first wave of ENHANCE data was released. See Eric's video on his blog:
http://blogs.theheart.org/posts/temple-of-the-ldl-cholesterol

In the end, Vytorin use will fall but for the wrong reasons. Absent information about "how to get there" before prescribing, LDL treatment will still be hit or miss. That's all the ENHANCE study showed. We know that reducing LDL is important but we still lack targeted treatments.

Dr. Marc Siegel, a senior fellow at the Center for Medicine in the Public Interest, is a practicing internist, an Associate Professor at the New York University School of Medicine and a fellow in the Master Scholars Society at New York University. Dr. Siegel is also a columnist for The Los Angeles Times and a frequent contributor to the Washington Post, USA Today, Slate, and many other publications. He is the author of False Alarm; the Truth About the Epidemic of Fear (top 20 books of 2005 - Discover Magazine) and Bird Flu: Everything You Need to Know About the Next Pandemic. Dr. Siegel appears regularly on CNN, the NBC Today Show, and the Fox News Channel. Dr. Siegel was a contributor to the U.S. Senate Finance committee investigation of the 2001 bioterror crisis.

In his essay, "The Virtual House Call," Dr. Siegel discusses many of the challenges facing the 21st century physician in the United States. Here is a free sample (yes, we here at drugwonks are still giving away free samples) of his discourse:

"I have a litmus test to check on my humanity. I call it the virtual house call. It isn’t an actual house call but it relies on similar notions of inconvenience in order to help a patient. Rarely do we have time these days to travel to a patient’s home. We must extend ourselves beyond our offices and our blackberries in caring for our patients in order to become truly empowered as physicians. This extension of self is the virtual house call.
Here is my litmus test: Every day I leave my office for a cup of coffee when I get restless. The coffee shop is one block south of where I practice. I ask myself what I would do if one of my patients, on his or her way to see me, suddenly collapsed right outside that same coffee shop I frequent and called my office from his cell phone while gasping for air.

Would I instruct my nurse to call 911, or would I run the same block I always walked?

Would I at least show as much commitment to my patient as I show to my caffeine habit?


I’ve never had to face this particular litmus test, but I certainly hope I would pass it. And each time I pick up the phone to check in on one of my patient, I’m conscious of a similar kind of litmus test. As I listen over the phone to the telling sounds of fast breathing or nervous coughing, I make determinations that my nurse or secretary could never make. I try to remain available, to not set strict limits. I’m convinced that continuity of care makes me a better doctor.

Dr. Siegel's entire composition can be found at both at the top of this page and at http://www.cmpi.org under the "Report" heading. The larger paper is titled, "The Hazards of Harassing Doctors."

No, really.

Health Affairs has announced that the NewsHour's Susan Dentzer will become the journal’s new editor-in-chief on May 1, 2008.

“It’s a great honor to be taking the reins at Health Affairs after John Iglehart and Jamie Robinson have done so much to make it the preeminent health policy journal of our time,” Dentzer said. “I’m delighted to become part of Project HOPE, and I look forward to working with the journal’s talented staff to continue to bring the best thinking and writing to bear on the top domestic and global health issues confronting us all.

Dentzer also serves on the Kaiser Commission on the Future of Medicaid and the Uninsured, and she is a member of the national advisory committee for the Robert Wood Johnson Foundation’s Investigator Awards in Health Policy Research. From 1993 to 2004, Dentzer was a member of the board of trustees for her alma mater, Dartmouth College, and she chaired the board from 2001 through 2004. As a Nieman Fellow at Harvard University in 1986 and 1987, Dentzer studied political economy, health economics, and business at the John F. Kennedy School of Government, Harvard Business School, and the Harvard School of Public Health.

Good luck Susan.

If I were a Carpenter or a Zucker or an Avorn, -- the three amigos who penned “Drug-Review Deadlines and Safety Problems” (NEJM, 2008; 358: 1354-61) – I’d be greasing up the old spin machine.

Consider the following from BioCentury Extra:

FDA refutes PDUFA safety study

FDA officials on Thursday criticized a study published in The New England Journal of Medicine that reports a statistically significant association between drug approvals near PDUFA deadlines and post-market safety problems.

The paper, by Daniel Carpenter of Harvard University and colleagues, concluded that drugs approved in the two months prior to their PDUFA deadlines were more likely to be withdrawn for safety reasons, to carry a subsequent black box warning, and to have one or more dosage forms discontinued by the manufacturer compared to drugs approved earlier or later. "Taken together, these findings suggest potential adverse effects of the deadlines governing FDA drug review," the paper said.

Clark Nardinelli, director of the economics staff in FDA's Office of Planning, told BioCentury that the agency has identified "at least two fundamental problems with the authors' data. We don't think their conclusions hold up." The paper misclassified a number of reviews as standard that actually had shorter deadlines because they were priority reviews, according to Nardinelli. When the reviews are classified correctly, the association between approvals near PDUFA deadlines and increased safety problems disappears, he said. The paper also understated the number of black box warnings, Nardinelli said. FDA plans to submit its data and conclusions to the NEJM and publish them on its Web site, spokesperson Christopher DiFrancesco said.

And all this time we thought it was the pharmaceutical industry playing fast and loose with data sets.

Well, as they say in Harvard Yard, "veritas."

We look forward to the FDA’s review … and hopefully to an apology from the authors and a retraction from NEJM.

Yeah, right.

Health policy analysts, physicians, pharmaceutical company executives, business leaders and government officials recently met in Washington at the CMPI-Duke University Patient-Centric Leadership Forum to discuss developments in this exciting field.

Previously we have shared some of the comments made by noted cardiologist Dr. Michael Weber (“Weber Grills”):

http://drugwonks.com/2008/02/weber_grills.html

and Dr. Ralph Snyderman, Chancellor Emeritus at Duke University and former Chancellor for Health Affairs at Duke University, President and CEO of Duke University Health System and James B. Duke Professor of Medicine (“The Greening of the American Health Care System”):

http://drugwonks.com/2008/03/the_greening_of_the_american_health_care_system.html

Today we are, as always, honored to share some of the comments offered by the hardest working man in American health care, Dr. Mark McClellan.

“We’ve got a healthcare delivery system that is organized the wrong way. It provides the wrong services with the wrong emphasis to get to personalized, predictive, preventative care. You can trace this back to the fact that reimbursement is wrong. We have payment incentives that encourage more intensity, especially after a health problem has developed and don’t have any real accountability for getting better results for patients’ health at the lowest overall cost. We have systems of choice in our healthcare system that don’t really give people a choice, where the policies, the coverage that you can get, is influenced by many factors beyond an individual’s preference.

There is a lot of potential for more targeted therapies, more prevention-oriented treatment strategies, more individualized predictive medicine. This is why I’m fundamentally optimistic about the future of our healthcare policies. As there is so much potential on the side of personalized, predictive patient-centric care, the discoveries are going to happen.

The question is simply how fast, and how quickly are we going to get to really irresistible pressure for the kinds of reforms that will close the gap between what we could do with the right reimbursement rules and the right ability for patients to choose their care?"

Yes, that is the question.

Full conference remarks will be available shortly. Watch this space for more details.

Senators Dick Durbin and Herb Kohl are proposing a federal grant program to allowing the hiring of physicians pharmacists and nurses who would to come up with "objective" promotional material (there's an oxymoron) about prescription drugs. These tax-payer paid reps would also go to doctor's offices to counter the promotion and use of higher-priced brand drugs that -- as the Senators claim -- are no more effective than generic versions.

If the goal is to increase generic prescribing shouldn't the generic industry be paying for these reps and the information? And if health care costs are the problem, why not send government paid reps to discourage use diagnostics, surgery and other services that are growing more rapidly than drug spending?

Oh wait, that's called rationing.

http://www.fiercehealthcare.com/story/senators-plan-bill-countering-pharma-detailing-tactics/2008-03-14

In CMPI’s new paper, “The Hazards of Harassing Doctors:Regulation and Reaction in Trans-Atlantic Healthcare," Dr. Alphonse Crespo, a Swiss physician, points out that focusing on cost-savings rather than patient care has unintended – but highly predictable consequences:

“Obsession with cost-containment has brought about regulatory measures that significantly affect the independence of German doctors. The “Drugs Saving Package” voted by the German parliament, introduces penalties for prescription of “expensive” drugs and rewards physicians who restrict their prescriptions to low-cost copy generics. This ethically objectionable legal gimmickry - akin to bribing physicians not to treat to the best of their ability - was one of the sparks of the doctor protest movement. A recent survey suggests that 65% of German physicians condemn bureaucratic tampering with prescriptions. Public perceptions echo their concerns. Questioned on this issue, 60% of people at large reckon that they will no longer get the best possible treatment from their doctors. Judging by media coverage, most Germans sympathize with their doctors' plight but express scepticism as to their ability to influence government health care policy and budgeting.”

Dr. Crespo’s complete essay and the complete paper can be found under the “Reports” heading at http://www.cmpi.org.

Interesting article in today’s Wall Street Journal on the use of genetic tools to resuscitate failed compounds.

Here how the story begins:

“As pharmaceutical makers find it increasingly difficult to bring new drugs to market, they are turning to genetic tools to seek uses for medicines that failed to make it out of the development pipeline.

The discovery of new links between genes and diseases can help not only to design new treatments, but to salvage drugs that are shelved when they come up short in clinical trials.”

And here’s the rest of the story:

http://online.wsj.com/article/SB120631682077958247.html?mod=dist_smartbrief

The better understanding of genetic tools (via a robust collaboration of industry, academia, and government) will both expedite failure (which lowers the cost of R&D) and provide a broader spectrum for success (which rewards it).

Sound familiar? Correct – the Critical Path.

Two interesting reader comments on the issue of government-sponsored counter-detailing as discussed in yesterday's blog entry "Close(d) Encounters."

Names have been withheld to protect the intelligent:

Dear DrugWonks:

What I think is interesting is whether this will become part of P4P proposals. If the government funds these counter-detailers, what happens if a physician refuses to see them? Are they reported to CMS? Are there repercussions for those physicians? Will they get more reimbursement if they see the government counter-detailers? If generic prescribing habits are part of P4P, as some propose, will this be part of it as well. Interesting to think about.

Dear DrugWonks:

I’d want to make sure the gov't detailers have to go by the same rules as the Rx companies -- FDA approved claims, FDA approved materials, no off label etc. Isn’t more info good?

PS, good luck getting a gov't employee to get in to see a doctor without pens and pizza if they don’t have cutting edge science to share

And if pharma detailers drive up the cost of Rx, won’t their detailers do the same?