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.

Important story in today’s Wall Street Journal on the topic of patients who suffer adverse events during clinical trials and the broader issue of informed consent. The article focuses largely on the story of Suzanne Davenport, a 71-year-old retired kindergarten teacher, diagnosed with Parkinson's in 1989.

Here’s a link:

http://online.wsj.com/article/SB120173515260330205.html?mod=hpp_us_pageone

One of the major issues discussed is standardization of consent forms. According to the Journal:

“Consent forms and compensation plans vary by institution. There have been sporadic calls to standardize these programs, but none have been widely adopted. The Institute of Medicine, a nonprofit group that advises the government on health policy, recommended in 2002 the creation of a "no fault" compensation system for injured subjects. The goal was to help trial participants resolve their claims quickly, without having to resort to lawsuits.”

But a far more difficult question (not discussed in the WSJ article) is that of patient therapeutic misperception. Can a patient really make an informed decision about what risks he or she is willing to take in the face of serious disease?

To investigate what patients really understand about the trials in which they have enrolled, leading Parkinson’s Disease researchers, ethicists Kim and Kieburtz, have been awarded a 2007 Michael J. Foundation grant to study ongoing participants of PD clinical trials that involve sham surgery controls. They plan to assess, by structured interviews, the potential for the therapeutic misconception i.e., why and how PD patients make their decisions regarding participation in sham surgery controlled studies

Regardless of the outcome, the biggest question remains the concept of what desperate patients want to understand and what they will do for a glimmer of hope.

From an editorial in the American Journal of Psychiatry.

Editorial
Demonstrating Drug Action
Carol A. Tamminga, M.D.


The questions that have arisen in the public and scientific literature lately about the use of SSRIs in children and adolescents are addressed for one of the currently available SSRIs by Wagner et al. The issue of whether it is effective to use SSRIs in childhood and adolescent depression has been repeatedly raised over the last years in the context of our field failing to produce clear efficacy answers in children. Depressed children are being treated with SSRIs in greater and greater numbers, without demonstrated efficacy in the age group. The difficulty of demonstrating efficacy with tricyclic antidepressants in children has fueled suspicions that there may exist an age-dependent resistance to treatment. The importance of this well-designed large study for therapeutic strategies in children and adolescents cannot be overstated. It is important that the methodology of this study is solid and the numbers adequate to test the efficacy question asked. The result that citalopram reduced depression more than placebo in this child and adolescent population provides a clear answer for physicians that will (in combination with results from additional studies) guide treatment decisions. It is especially gratifying to see an early onset of action at 1 week of treatment, suggesting an advantage that can be followed up in future studies. This study also set a high methodologic standard for psychiatric diagnosis in pediatric studies. It would be an understatement to say that more such studies are needed.

One would always wish for more in terms of information from drug trials in psychiatric diseases. A common physician complaint about these trials is that they fail to sufficiently inform clinical practice because of restricted entry criteria, fixed-dose design, and limited duration of treatment. It is true that initial registration trials have a goal of demonstrating superiority over placebo to become approved for the market. But this does not rule out additional Phase 4 studies done in large enough patient cohorts to fully inform pressing clinical issues. How do comorbid conditions alter drug response? What treatments are effective in medication nonresponders? What kinds of actions can be expected with long-term treatment? It will be important for industry to address these kinds of Phase 4 questions for clinical use as well as the registration trials.

One particular issue in our field makes informative clinical trials particularly difficult. This is that we do not know what exactly we are treating in terms of its biology. Psychiatric diagnoses are not based on molecular pathology (rather, phenomenology), and new drugs are not directed toward known, disease-related molecules (rather, toward hypotheses). Therefore, we may not be recruiting the correct patient populations for a particular treatment nor have a drug directed toward the disease pathophysiology. Moreover, we may not be measuring anywhere near the optimal outcome measures in our trials (e.g., consider the constraint of only measuring "fatigue" in the treatment of anemia, and not having a RBC count). Nonetheless, even though we do not yet have our molecular targets, we cannot give up on drug development. Indeed, we already have treatments for our diseases, and these may be better treatments than we deserve, based on the state of our knowledge. We need now to hone the treatments that we have and develop the valuable clinical trial methodologies to carry us into the future. Meanwhile, we need to translate the rich basic knowledge accumulating in neuroscience into advances for therapeutics.

http://ajp.psychiatryonline.org/cgi/content/full/161/6/943?etoc

Who do you trust? The New York Times editorial page or the consensus statement of the American College of Cardiology which said with regard to Vytorin:

"The study involved 720 patients with heterozygous familial hypercholesterolemia and showed no significant difference in the primary endpoint between patients treated with ezetimibe and simvastatin versus patients treated with simvastatin alone over a two-year period. The study was designed to prove that Vytorin could slow the growth of plaque in carotid arteries supplying the brain more than simvastatin alone. Media reports indicate that the results of the trial show no benefit from the combination of ezetimibe (Zetia) and simvastatin (sold together as Vytorin) over simvastatin alone.

The American College of Cardiology recommends that major clinical decisions not be made on the basis of the ENHANCE study alone."

According to the American College of Cardiology (ACC), this study deserves serious thought and follow-up. The overall incidence rates of cardiac events were nearly identical between both treatment groups, and both medicines were generally well tolerated. There should no be reason for patients to panic. The difference in IMT changes between the simvastatin group and the Vytorin group was 0.006 mm vs. 0.011 mm.

Health care professionals should speak to their concerned patients using this drug. The ACC is also releasing a public statement explaining that this is not an urgent situation and patients should never stop taking any prescribed medications without first discussing the issue with their health care professional. Further research will be needed in this area to provide conclusive evidence about which lipid lowering strategy is preferred (statin alone vs. statin plus ezetimibe).

Furthermore, the ACC notes that this trial is an imaging study and not a clinical-outcome study. Conclusions should not be made until the three large clinical-outcome trials are presented within the next two to three years. The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can only tolerate a low dose statin.

On the subject of endpoints and markers. The Critical Path is not about using surrogate endpoints. Anyone who has listened to Dr. Woodcock more than once knows it is about finding and qualifying biomarkers -- molecular and imaging -- that predict disease progression and outcome as well as response to treatment -- as well as developing novel statistical ways that can be deployed across divisions and technologies to advance understanding of technology impact on disease.

The issue in the ENHANCE study was whether or not imaging studies were accurate measures of disease progression in this small population. Nothing more or less. In this regard, development of better standards and predictive imaging studies will help advance their use in clinical trials. Also let's remember that Dr. Nissen, who has trashed the results might be a bit biased since his own imaging studies demonstrated a regression of atherosclerosis by reducing LDL levels with another drug, something the NY Times failed to point out. And let's remember Dr. Nissen also tossed out imaging studies in another clinical trial looking at plaque regression because they were unreadable, so he just looked at the results of the readable ones.

At the risk of repeating myself again and again -- here's a link to the story we repeated when the MSM was looking for a Vytorin coverup months ago.

http://www.thestreet.com/pf/comment/adamfeuerstein/10195643.html

The problem with the Atherogenic drug that Nissen worked on was the same one -- more or less -- the scientists running the ENHANCE study struggled with. Namely, the statistical correlation was hard to measure because of the unwieldy nature of the biomarker. In each study, patients taking the drug did better than patients taking a placebo on most endpoints, just not on the endpoint most difficult to measure. But unlike the Nissen re-analysis, ENHANCE did not do an interim analysis with fewer patients to produce a benefit. The debate was whether or not to chuck the analysis altogether because of questions about the reliability of the biomarker.

Which is what the Critical Path is all about.

No need to panic or disregard your doctor in favor of the medical advice dispensed by the fearmongers and Pharm-haters on the NY Times editorial page.

From the pages of FDA News ...

Critical Path Wants Adaptive Clinical Trial Designs, Temple Says

The FDA is encouraging the use of adaptive trials, saying the practice will modernize the development process and shorten the time needed to show a drug is effective. The agency’s associate director for medical policy, Robert Temple, said the Critical Path Initiative encourages the use of this kind of trial when researchers use accumulating data to modify the ongoing trial. Temple, speaking at the Critical Path Executive Briefing sponsored by FDAnews and the Center for Medicine in the Public Interest, said the FDA is working on an adaptive design guidance it promised to release in 2008.

Some of the more familiar adaptations include changing sample sizes based on variance and starting and dropping extra trial groups. When researchers determine a drug effect is present in a population subset, they can adapt the trial by modifying the trial’s entry criteria or increasing the number of patients assigned to receive the effective treatment.

While almost every clinical trial uses enrichment in some way to improve the trial’s patient population, there are more steps that can be taken to increase the chances a drug effect is detected, Temple said. Some enrichment efforts can decrease variants while others can choose high-risk patients or patients more likely to respond to treatment because of some genetic characteristic.

“Everyone agrees about finding the people who are most likely to respond … it enormously enhances the power of the study,” Temple said. Enrichment will help researchers by decreasing heterogeneity and identifying a population that responds to the treatment.
For example, researchers can screen patients with the treatment first and then enroll them in the study if they respond to the drug. In addition, researchers can study a large group of patients and only randomize those with a good response.

Scientists are beginning to be able to search for genetic characteristics or other factors that will predict a patient’s response to a drug, Temple said. Part of the Critical Path Initiative is to identify biomarkers and determine why some patients and not others experience adverse events with the same drug.

Researchers can select trial subjects based on either understanding of a disease or a drug mechanism, but they also can run a trial in patients to link a genetic baseline finding with a drug response, Temple added.

one issue which is once again being overlooked amid the outcry against an unexpected possible side effect of a drug is the efficacy of the drug itself. The reason I am not stopping Avandia on every patient I have who is taking it is not just that the possible deleterious effect on the heart remains unproven, that the association, as Bob Goldberg has said, is not at the level of cause/effect. there is another problem - that the glitazones are great drugs, that we already saw Rezulin tarred and feathered and ultimately hung from a tree until dead. Is Avandia to be the new Rezulin, followed by Actos, arguably the most effective of the three.
By the way, how many lives did Rezulin save because it was an effective diabetes drug verses how many liver deaths were associated with its use? This is not a rhetorical question - it was removed after a handful of possible cases of severe liver damage.
Believe me, I am not championing drug side effects, nor am i against the idea of widening post market initiatives. It is clear that unexpected side effects need to be watched out for, and that drug safety is an ongoing concern that involves more than just the target organ.
But drug safety and cost/benefit analyses mean looking at more than just a weakly observed mathematically determined association. These shadows will be found in many more places the harder we look for them. And great drugs will be unfairly targeted and destroyed. The cost is too high. Two TZDs down. One left to go. By the way, did I forget to mention that these drugs are perhaps the best drugs we have for type 2 diabetes - i see that I began my post this way - so I've come full circle.

Late last month, an important study in JAMA showed that patients in a high LDL cholesterol group from 130 to 160 did not show a progression of carotid plaque when receiving rosuvastatin compared with control. This study was a breakthrough in terms of primary prevention though the results are not surprising, and many internists, myself included, were already treating many of the members of this group with statins. Carotid plaque is predictive of coronary plaque, and previous studies have shown plaque stabilization with atorvastatin in patients with heart disease leading to a diminishing of subsequent cardiac events. (secondary prevention)

Here is the new JAMA study on rosuvastatin - it would be interesting to follow this up with a study that looked at whether bringing down LDL to less than 80 with diet alone, gave the same results in terms of plaque as when a statin is used.

http://jama.ama-assn.org/cgi/content/full/297/12/1376

Here's an interesting story by the Healthday reporter which was published in the Wash Post, Forbes, and several other places.

I was quoted extensively about neuraminidase inhibitors in the context of cautioning overuse based on FEAR, but of course avocating appropriate use.

Resistance patterns are emerging in Japan in Influenza B strains according to a new study out of the University of Tokyo.

http://www.washingtonpost.com/wp-dyn/content/article/2007/04/03/AR2007040301282.html