Clinical Trials News

Pharmion Ltd Withdraws Its Marketing Authorisation Application For Orplatna (satraplatin), Europe

2008-08-05T13:51:00.000-07:00

Image via WikipediaThe European Medicines Agency (EMEA) has been formally notified by Celgene Europe Ltd of Pharmion Ltd's decision to withdraw the application for a centralised marketing authorisation for the medicine Orplatna (satraplatin) 10 mg and 50 mg capsules. Orplatna was expected to be used, in combination with prednisone and prednisolone, in the treatment of patients with metastatic hormone-refractory prostate cancer who have failed prior chemotherapy.

The application for marketing authorisation for Orplatna was submitted to the EMEA on 22 June 2007. At the time of the withdrawal, it was under review by the Agency's Committee for Medicinal Products for Human Use (CHMP).

In its official letter, the company stated that the withdrawal of Orplatna was based on the CHMP's view that the data provided do not allow the Committee to conclude a positive benefit-risk balance for Orplatna for the applied indication.

More information about Orplatna and the state of the scientific assessment at the time of withdrawal will be made available in a question-and-answer document. This document, together with the withdrawal letter from the company, will be published on the EMEA website in due course.

Notes

1. Pharmion Ltd was acquired by Celgene Europe Ltd in March 2008.

2. Withdrawal of an application does not prejudice the possibility of a company making a new application at a later stage.

3. This press release, together with other information on the work of the EMEA, can be found on the EMEA website: http://www.emea.europa.eu

Redefining Quality — Implications of Recent Clinical Trials

2008-06-09T10:58:00.000-07:00

Image via WikipediaSimple approaches to patient care are better — except when they are not. Recent clinical studies are leading to a reexamination of the paradigm whereby efforts to prevent vascular disease focus on the achievement of particular levels of risk factors such as low-density lipoprotein (LDL) cholesterol, systolic blood pressure, and glycated hemoglobin. Although these factors and their levels are important determinants of the development and progression of vascular disease, it is increasingly apparent that the specific strategies used to modify them make a critical difference in patient outcomes. This insight has implications for clinical practice, performance measurement, and regulatory requirements.

The conventional wisdom, which emerged from epidemiologic studies of risk factors and the subsequent successful trials of certain strategies for risk-factor modification, has been that the clinician's key focus ought to be on reducing risk factors below specific levels. This approach, however, neglects the importance of which specific strategies are used to modify these factors. A clinical trial is ultimately a test of a strategy, and we should not be surprised that different strategies may have different effects on patients beyond their effect on risk-factor levels.

Awareness of this issue was boosted on December 2, 2006, the day Pfizer stopped the study named ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) and all other trials involving torcetrapib, which until then had been seen as a promising agent that lowered LDL cholesterol levels and raised high-density lipoprotein (HDL) cholesterol levels. ILLUMINATE was halted because patients receiving torcetrapib plus atorvastatin had a higher mortality rate than those receiving atorvastatin alone — despite 72% increases in HDL levels and 25% decreases in LDL levels.
ILLUMINATE is not alone in raising questions about the wisdom of patient care that prioritizes target levels of some risk factors over attention to the way in which those levels are achieved. The Women's Health Initiative revealed that hormone-replacement therapy, which reduces LDL cholesterol levels, increased the risk of cardiovascular disease.2 Another study, called ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia), showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin, as compared with simvastatin alone, even though the combination did result in a greater reduction of LDL cholesterol. Rosiglitazone improves glucose control, but it may also be associated with increased cardiovascular risk.3 Adding an angiotensin-receptor blocker to an angiotensin-converting–enzyme inhibitor may produce a greater reduction in blood pressure, but it may not reduce cardiovascular risk and it increases the risk of other adverse events.4

The importance of understanding clinical trials as tests of strategies has assumed even greater prominence because of two studies being reported on in this issue of the Journal — ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). These two studies (pages 2545–2559 and 2560–2572, respectively) tested the hypothesis that specific strategies involving the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus. The studies, which used different pharmacologic strategies, found that the tight control achieved did not reduce the risk of macrovascular complications. The ACCORD study's intensive control strategy was associated with a higher risk of death, which led to early discontinuation of this part of the study. The ADVANCE study's findings indicate that its strategy may reduce the risk of worsening renal function at the cost of an excess risk of hypoglycemic events.

Thus, the risk–benefit ratio of interventions designed to modify risk factors can vary depending on the type and number of medications and other approaches that are concurrently incorporated. In particular, some medications may have beneficial or harmful effects beyond their effect on a risk factor. Moreover, the strength of the evidence supporting particular strategies varies. Some strategies are known to improve patient outcomes, whereas others are known to affect only risk-factor levels or other intermediate outcomes. We are now beginning to appreciate that a strategy's effect on a risk factor may not predict its effect on patient outcomes.

Clearly, the way in which risk factors are modified really does matter. Lifestyle interventions may have few risks, but we cannot assume the same for drugs — and drug-related risks are not always known or appreciated. For example, the tendency of torcetrapib to cause blood pressure to rise and potassium levels to fall attracted much more attention after December 2006 than it had previously. In addition, medications may have interactions with other drugs, either directly or through their effect on patient adherence to treatment regimens.

As a result of these research advances, clinicians are now in a quandary. We prefer our clinical practice to be based on strong evidence. In the interest of promoting good care, we have constructed guidelines and performance measures that encourage treatment geared toward achieving ambitious goals for levels of glycated hemoglobin, lipids, and blood pressure. These treatment goals generally do not specify the strategy that should be used to reach the target. Statins are preferred in the reduction of LDL cholesterol, but guidance on their use is not strict.5 If strategy matters, then guidelines should reflect this fact — and performance measures should be changed as well. After all, these measures are intended to hold clinicians accountable for practices whose benefits are widely recognized as far outweighing their risks.

How, then, should guidelines and performance measures change? First, we should no longer support the use of targets without reference to the strategies used to achieve them. Guidelines and performance measures should reflect the evidence about interventions that are known to be beneficial. For example, guidelines for lowering lipid levels should be based on tested strategies and should make it clear that the strategies with the strongest evidence are preferred. A quality measure that incorporated the use of statins into an assessment of lipid-level control would be more scientifically sound than the simple assessment of the proportion of a physician's or practice's patients in whom a specific LDL cholesterol level was reached by any strategy. A quality measure for tight glucose control should require evidence that a proven strategy provides a strong net benefit for patients. We know that we are setting a high standard for developers of performance measures, but advances in our knowledge demand nothing less.

Second, guidelines and performance measures should incorporate more sophisticated and explicit considerations of the risks of disease and adverse consequences posed by the intervention. In patients with a low likelihood of a particular poor outcome, an intervention designed to protect against that outcome is unlikely to provide substantial benefit — so if the intervention carries even a small risk, this risk can offset or even outweigh the benefit. In sicker patients and those with more complex conditions, certain interventions (such as maintenance of tight glucose control) may be more likely to produce adverse effects than they would in healthier patients, either directly or through their effect on adherence. For these patients, we need evidence that the strategy is safe and has a substantial net clinical benefit despite the greater risks of treatment.

The assessment of net clinical benefit should be based on events averted or lives improved. The promulgation of those strategies that are shown to be effective will serve as an incentive for drug and device developers to provide evidence about patient outcomes, not just about how a drug or device affects intermediate outcomes. Moving practice toward evidence-based strategies and becoming more accountable for what we do for patients represent important advances in our delivery of health care, but we must ensure that in implementing quality measures we are always acting in the patient's best interests. ACCORD, ADVANCE, and other recent studies remind us that practice is complex and that ultimately we need to understand a strategy's effects on people, not just on surrogate end points.

No potential conflict of interest relevant to this article was reported.

Source Information

Dr. Krumholz is a professor of medicine at Yale University School of Medicine and director of the Center for Outcomes Research and Evaluation at Yale–New Haven Hospital — both in New Haven, CT. Dr. Lee is network president of Partners HealthCare System in Boston and an associate editor of the Journal.

Exploiting a Research Underclass in Phase 1 Clinical Trials

2008-05-29T07:50:00.000-07:00

In November 1996, the Wall Street Journal reported that Eli Lilly was paying homeless alcoholics from a local shelter to participate in safety testing of new drugs at its trial site in Indianapolis.1 "These individuals want to help society," asserted Lilly's director of clinical pharmacology. The subjects, however, said they took part for easy money and free room and board. Although Lilly reportedly offered the lowest per diem in the business, it managed to attract poor subjects from all over the country.1 The medical director of the local Homeless Initiative Program said Lilly had created a "shadow economy" of paid human subjects.

Today, the Lilly episode seems like an early warning about an emerging set of ethical problems. Over the past decade, clinical trials have moved from universities to private testing sites, the pressure to recruit subjects quickly has intensified, and ethical oversight has been outsourced to for-profit institutional review boards (IRBs). Payment to subjects has escalated, creating "shadow economies" in cities throughout North America and elsewhere. In 2005, Bloomberg Markets reported that SFBC International, a contract research organization, was paying immigrants to participate in drug trials under ethically questionable conditions in a dilapidated Miami motel. A few months later, nine apparently previously healthy subjects at an SFBC subsidiary in Montreal contracted latent tuberculosis during a trial of an immunosuppressant. In 2006, six healthy subjects required intensive care in a phase 1 trial of a monoclonal antibody at a London facility run by the contract research organization Parexel. For all the ethical debate over these cases, however, few commentators have addressed the most troubling question: Is it ethically problematic to pay poor people to test the safety of new drugs?

Paying study subjects is not a new practice, but neither is it uncontroversial. According to regulators, payment should not be so high as to become an "undue inducement," lest subjects enroll in risky, unpleasant, or degrading trials against their better judgment. But this standard gives IRBs little practical guidance: a sum of money that the wealthy can easily resist may be very tempting for poorer people. Keeping payments low, however, seems unfair to the poor, who submit to trials precisely because they need the money. And whether or not such people are being unduly induced, the larger question is whether they are being exploited.

To exploit people is to take unfair advantage of them, but there is no consensus that current trial arrangements are unfair. Defenders of the status quo argue that people who enroll in trials have agreed to their conditions, that they get paid enough to make it worth their while, and that they are made better off by the arrangement. Nevertheless, there are good reasons to believe that poor subjects are being exploited.

First, poor people are less likely than wealthier ones to get access to the drugs in question, if and when they are approved. Volunteers are unlikely to have full-time employment or, therefore, to have health insurance. Placing the burden of safety testing on the poor appears to contravene article 19 of the Declaration of Helsinki, which states that medical research is ethically justified only if there is a reasonable chance that the population in which it is conducted will benefit from the results.

Second, the U.S. oversight system is not well equipped to monitor a highly competitive, market-based, multinational research industry. The Office for Human Research Protections has no jurisdiction over privately sponsored studies, and the Food and Drug Administration inspects only about 1% of clinical trials.2 IRBs, the most important bodies charged with protecting subjects, were designed primarily to review trial design, risk–benefit ratios, and informed-consent documents. Recent research scandals — which have been uncovered largely by investigative reporters rather than regulators — have concerned a very different set of issues: fraud, conflicts of interest, unfair payment practices, and unsafe or degrading trial conditions. Such problems are magnified still further when studies are conducted at private testing sites and reviewed by for-profit IRBs that are financially dependent on research sponsors.

Third, even though the purpose of phase 1 trials is to test whether new drugs are safe, most sponsors apparently do not provide free care or treatment for subjects who are injured in these trials. In fact, no agency is even tracking injuries in phase 1 trials, much less the long-term health of people who volunteer for many trials over a period of years. A recent study commissioned by the Department of Health and Human Services showed that only 16% of academic health centers provide injured subjects with free care. None compensate injured subjects for pain and suffering or lost wages.3 Although no comparable data are available for private research sponsors, there is little reason to believe that private sponsors are much more generous4; indeed, many include disclaimers in their consent forms indicating that subjects retain responsibility for their own medical care.

Most of these problems can be seen as consequences of the transformation of clinical research into a business. Many subjects in phase 1 trials today see their participation as a job.5 They must pay taxes on their trial income, and sponsors often require them to sign a form acknowledging their status as "independent contractors." The payment has become high enough to make participating in trials more lucrative than holding a minimum-wage job, even if subjects abide by the requirement that they wait 30 days between trials. Yet subjects get none of the rights or benefits that come with a good job, such as workers' compensation, the right to unionize, disability benefits, or health insurance. Subjects whose livelihoods depend on trial income are often reluctant to drop out of trials that turn out to be risky or unpleasant, especially if they have traveled some distance to the trial site and have invested a substantial amount of money in accommodations while waiting to enter the trial. Subjects have little incentive to be truthful about their medical history or health status because known medical problems may preclude their participation in a study. Nor do they have anyone to go to with complaints. Many say they are reluctant to complain to sponsors about poor conditions for fear of being excluded from future trials. For similar reasons, they are reluctant to go to a lawyer, even if a trial goes seriously wrong.4

Without actually intending to do so, policymakers have allowed participation in clinical trials to become something very close to a job. Sponsors call subjects' payments "compensation" to suggest that they are merely reimbursing participants for expenses and inconvenience, even as they fill studies with unemployed people who depend on trial income to make ends meet. They refer to paid subjects as "volunteers," implying that participation is a freely chosen act of altruism, whereas most subjects indicate that they take part in trials for the money. Regulators allow sponsors to use money to attract subjects but do not require them to provide the kinds of benefits that subjects would demand if they had more power. The result is what one Philadelphia trial subject describes as "a mild torture economy." "You are not being paid to do something," he explains. "You are being paid to endure."5

No potential conflict of interest relevant to this article was reported.

Source Information

Dr. Elliott is a professor at the Center for Bioethics at the University of Minnesota, Twin Cities. Dr. Abadie is an anthropologist and independent scholar who recently completed a research fellowship in the Bioethics Research Program, Mayo Clinic, Rochester, MN.

KaloBios Completes Patient Dosing In Its U.S. Phase 1 Trial Of Its Third Drug Candidate, KB003

2008-04-30T11:13:00.000-07:00

KaloBios Pharmaceuticals, Inc., a privately held biopharmaceutical company, announced that the company has completed dosing subjects in a U.S. Phase 1 clinical trial of its third drug candidate, KB003. The study is a placebo-controlled, single-dose, dose-escalation Phase 1 trial in healthy volunteers, with safety and immunogenicity as primary endpoints.

KB003 is a Humaneered™ monoclonal antibody targeted to GM-CSF, and it shares the same epitope (target) and pharmacokinetic properties with KB002, its chimeric (mouse) precursor. They are part of a major development program that collectively includes five Phase 1 and Phase 2 proof-of-principle clinical trials for inflammation-related diseases, including persistent asthma and rheumatoid arthritis. Animal studies have suggested the drug candidate also has potential in multiple sclerosis, chronic obstructive pulmonary disease ("COPD"), psoriasis, and other indications.

"This antibody is another example of the power of Humaneering™ technology," said Geoffrey Yarranton, KaloBios' Chief Scientific Officer. "We believe that high affinity antibodies that are close to human germline will be preferred when choosing antibody treatments for chronic diseases in large patient populations. We are especially excited about the use of this antibody in future repeat-dose chronic clinical trials in humans."

"We now have the most comprehensive clinical research program in the world for targeting GM-CSF," said Tillman Pearce, KaloBios' Chief Medical Officer. "We have treated our last patient in our Phase 1/2 rheumatoid arthritis trial, are making great progress with our Phase 2 persistent asthma trials, and have other confidential clinical trials underway. We can now leverage the data that we obtain from these KB002 studies to guide our KB003 multiple-dose trials."

About KaloBios

KaloBios Pharmaceuticals, Inc., a U.S. based, private monoclonal company, uses its proprietary platform technology to develop first or best-in-class human antibody therapeutics. The company has multiple programs that are in five Phase 1/2 clinical trials: KB001 is an anti-infective for Pseudomonas aeruginosa infections being tested in cystic fibrosis and soon to be tested in intensive care patients on a ventilator, and KB002 and KB003 are being evaluated in inflammatory conditions such as rheumatoid arthritis and asthma. The company's Humaneering™ technology offers advantages over other methods of human antibody creation in terms of immunogenicity, potency, and manufacturing yields.

FDA Says Heparin Contamination Is A Worldwide Problem

2008-04-22T12:12:00.000-07:00

Image via Wikipedia

The US Food and Drug Administration (FDA) said yesterday, Monday 21st April, that contamination of the blood thinner heparin, used in surgical and dialysis procedures to stop blood clots, is a worldwide problem. The agency stressed while there is still no scientific evidence of a direct link between the contaminant, and dozens of deaths and hundreds of severe allergic reactions in the US, they have established a credible route through which such a link might be possible.

Earlier this year, there was a significant increase in reported deaths and adverse reactions in the US following use of batches of heparin product made by Baxter International.

Baxter implemented a phased recall of its heparin products, and lab tests by the FDA and others showed that the products linked to the adverse reactions and deaths contained a contaminant, a form of chondroitin sulfate, derived from animal cartilage. The contaminant was found in the heparin raw ingredient made by a Chinese subsidiary owned by the Wisconsin based company Scientific Protein Laboratories (SPL). The Chinese subsidiary is called Changzhou SPL.

Dr Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research, told the press yesterday that the agency had now "established a mechanism by which we think this contaminant could cause these adverse events", reported CNN, but she did not go so far as to say there was certain proof, only that the route was possible.

Earlier yesterday, a senior Chinese health official, Jin Shaohong, said that the contaminant that had been found in batches of the Baxter's blood thinner, thought to be an oversulfated form of chondroitin sulfate, was not to blame for the deaths, because according to China's own investigations, some of the adverse events followed use of heparin that did not contain the contaminant.

Woodcock disputed this assertion, and told the press that the Chinese tests "did not find contamination, but we are fairly certain because of multiple labs doing the testing that this lot contains contaminants".

Yesterday the FDA CDER website posted a number of documents updating the heparin situation.

One is a world map highlighting 11 countries where heparin containing the contaminated active ingredient from China has been found. The 11 countries are: Australia, Canada, China, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand and the USA.

Another FDA CDER document posted yesterday updates the US figures on the adverse events and deaths linked to the drug. This details the adverse event reports, including deaths, reported to the FDA between 1st January 2007 to 13th April 2008 (note this is according to date of report and not date of event; some reports came in later, once awareness of the situation increased).

Altogether there have been 131 reports of deaths in the US (from any cause, that is with or without allergic reaction) following use of heparin since 1st January 2007, with 123 of them reported on or after 1st January 2008.

81 of the deaths included one or more symptoms of allergic reaction or high blood pressure. 78 of these were reported after 1st January 2008.

The FDA stressed that the fact allergic reaction or high blood pressure were reported does not mean these caused the deaths.

A third document posted on the FDA CDER website yesterday was a letter to Changzhou SPL, stating that a recent inspection by US FDA officials had found significant deviations between procedures at the plant and US practice in the manufacture of active pharmaceutical ingredients (APIs).

The letter said the company had not adequately evaluated the suppliers of the crude materials, and the crude material itself, and that the manufacturing equipment was not suitable for purpose. It said that tanks to make the API were certified as clean, but "unidentified material" was found clinging to their inside surfaces.

The letter warned that until the irregularities are put right, shipments from the plant will be refused entry into the US.

Woodcock told the press she would not comment on the details of evidence collected so far because the better thing to do is wait until it is published in scientific literature when other scientists have had a chance to review it.

She also said the agency was not "able to rule out the fact that there could be other problems leading to these adverse events", reported CNN.

This has also been the position maintained by Baxter, which to a certain extent reflects what the Chinese authorities said yesterday, where the possibility that manufacturing problems after the raw ingredient has left China, and the condition of the patients themeselves, could be contributing factors.

Woodcock said she hoped that scientific dialogue will help to overcome some of the skepticism about the FDA suggestions.

While it is not possible to trace a direct link to the adverse events and deaths, since the product recall, the number of deaths and adverse events reported to the FDA has returned to the previous level.

What People Should Know When Enrolling In Clinical Trials

2008-04-18T04:17:00.000-07:00

An article published in the March 2008 issue of the Journal of Medical Ethics explores often-neglected aspects of the "therapeutic misconception," an ethical problem present in many clinical research studies. This misunderstanding arises when research subjects believe they will be receiving optimal medical care as opposed to being participants in an experimental trial whose main goal is the benefit of future patients. Such misconception can lead subjects to underestimate risks and overestimate benefits.

Discussions on the therapeutic misconception usually center on whether it invalidates the consent of subjects. But lead author Dr. Inmaculada de Melo-Martín of the Department of Public Health at Weill Cornell Medical College and co-author Dr. Anita Ho of the Department of Philosophy at the University of British Columbia argue that focusing only on how the therapeutic misconception affects informed consent doesn't capture the ethical complexity of the problem.

Equally significant are negative consequences to subjects, researchers and others resulting from misplaced trust, especially if this trust is exploited in order to recruit and retain subjects. The manipulation of subjects' misplaced trust, whether intentional or not, can undermine the trustworthiness of the research enterprise. It is therefore crucial for investigators and institutions to make efforts and employ strategies that are likely to dispel the therapeutic misconception and not to enroll those who still suffer from the misconception.

Cancer Trials Found To Have Flaws In Studies' Design And Analysis

2008-03-26T08:33:00.000-07:00

A new study reviewing 75 group-randomized cancer trials over a five-year stretch shows that fewer than half of those studies used appropriate statistical methods to analyze the results. The review suggests that some trials may have reported that interventions to prevent disease or reduce cancer risks were effective when in fact they might not have been.

More than a third of the trials contained statistical analyses that the reviewers considered inappropriate to assess the effects of an intervention being studied. And 88 percent of those studies reported statistically significant intervention effects that, because of analysis flaws, could be misleading to scientists and policymakers, the review authors say.

"We cannot say any specific studies are wrong. We can say that the analysis used in many of the papers suggests that some of them probably were overstating the significance of their findings," said David Murray, lead author of the review study and professor and chair of epidemiology in the College of Public Health at Ohio State University.

"If researchers use the wrong methods, and claim an approach was effective, other people will start using that approach. And if it really wasn't effective, then they're wasting time, money and resources and going down a path that they shouldn't be going down."

Murray and colleagues call for investigators to collaborate with statisticians familiar with group-randomized study methods and for funding agencies and journal editors to ensure that such studies show evidence of proper design planning and data analysis.

The review appears online in the Journal of the National Cancer Institute.

In group-randomized trials, researchers randomly assign identifiable groups to specific conditions and observe outcomes for members of those groups to assess the effects of an intervention under study.

These trials are used to investigate interventions that operate at a group level, manipulate the social or physical environment, or cannot be delivered to individuals in the same way a pill or surgical procedure can. For example, a group-randomized trial might study the use of mass media to promote cancer screenings and then assess how many screenings result among groups that receive different kinds of messages.

In analyzing the outcomes of such trials, researchers should take into account any similarities among group members or any common influences affecting the members of the same group, Murray said. But too often, this review found that the common ground among group members was not factored into the final statistical analysis.

What can result is called a Type 1 error, when a difference between outcomes in groups is found that doesn't really exist.

"In science, generally, we allow for being wrong 5 percent of the time. If you use the wrong analysis methods with this kind of study, you might be wrong half the time. We're not going to advance science if we're wrong half the time," said Murray, also a member of the Cancer Control Program in Ohio State's Comprehensive Cancer Center.

The review identified 75 articles published in 41 journals that reported intervention results based on group-randomized trials related to cancer or cancer risk factors from 2002 to 2006. Thirty-four of the articles, or 45 percent, reported the use of appropriate methods used to analyze the results. Twenty-six articles, or 35 percent, reported only inappropriate methods were used in the statistical analysis. Eight percent of the articles used a combination of appropriate and inappropriate methods, and nine articles had insufficient information to even judge whether the analytic methods were appropriate or not.

"Am I surprised by these findings" No, because we have done reviews in other areas and have seen similar patterns," Murray said. "It's not worse in cancer than anywhere else, but it's also not better. What we're trying to do is simply raise the awareness of the research community that you need to attend to these special problems that we have with this kind of design."

The use of inappropriate analysis methods is not considered willful or in any way designed to skew results of a trial, Murray noted.

"I've seen creative reasons people give in their papers for using the methods they use, but I've never seen anybody say it was done to get a more significant effect. But that's what can happen if you use the wrong methods and that's the danger," he said. "What we want to know from a trial is what really happened. If an intervention doesn't work, we need to know that, too, so we can try something else."

The review also is not an indictment of the study design. Murray is a proponent of such trials and was the first U.S. expert to author a textbook on the subject (Design and Analysis of Group-Randomized Trials, Oxford University Press, 1998).

He also is a co-investigator on three group-randomized trials in progress at Ohio State. Two trials use specific clinics as the assigned groups. One is analyzing the effectiveness of having specially trained guides help cancer patients negotiate the health-care system. The second is investigating the effectiveness of aggressive physician promotion of colorectal cancer screening for patients with cancer risk factors. A third trial will use Appalachian counties as groups to compare the effectiveness of a media campaign to promote colorectal cancer screenings.

"We're not trying to discourage people from using this design. It remains the best design available if you have an intervention that can't be studied at the individual level," Murray said.

First Study To Investigate The Effect Of Father's Diet On Chromosomal Abnormalities In Sperm Reveals Link With Folate A Vitamin B

2008-03-23T08:55:00.001-07:00

Researchers have found an association between a vitamin found in leafy green vegetables, fruit and pulses [1] and levels of chromosomal abnormalities in men's sperm. Men who consumed high levels of folate (a water-soluble B vitamin that occurs naturally in food) and folic acid (the synthetic form of the vitamin) tended to have lower levels of abnormal sperm where a chromosome had been lost or gained (known as aneuploidy).

Writing in Europe's leading reproductive medicine journal, Human Reproduction Thursday 20 March, the authors say estimates suggest that between 1-4% of sperm in a healthy man have some type of aneuploidy, but there are large variations among individuals, the mechanisms are poorly understood and little is known about the effects of men's diet on their sperm. [2] In the first study of its kind to investigate the relationship between sperm aneuploidy and paternal diet, they analysed sperm samples from 89 healthy, non-smoking men and questioned them about their daily total intake (from diet and from vitamin supplements) of zinc, folate, vitamin C, vitamin E and beta-carotene.

One of the principal investigators of the study, Brenda Eskenazi, Professor of Maternal and Child Health and Epidemiology and Director of the Center for Children's Environmental Health at the School of Public Health, University of California, Berkeley, USA, said: "We found a statistically significant association between high folate intake and lower sperm aneuploidy: there was increasing benefit with increasing intake, and men in the upper 25th percentile who had the highest intake of folate between 722-1150 micrograms, had 20-30% lower frequencies of several types of aneuploidy compared with men with a lower intake.

"However, this study cannot prove that high folate intake caused the lower sperm aneuploidy levels, only that there is an association. This is the first study of its kind and the results indicate the need for further research, especially a randomised controlled trial, on this topic."

The researchers found no consistent associations between intakes of zinc and the other vitamins and sperm aneuploidy.

Prof Eskenazi said: "While the importance of maternal diet on reproduction, especially folate intake, is well known, the results of our study suggest the importance of studying paternal nutrition when considering male-mediated developmental consequences. In previous studies, we and others have shown that paternal micronutrient intake may contribute to successful conceptions by improving the quality of the sperm. This study is the first to suggest that paternal diet may play a role after conception in the development of healthy offspring." [3]

The current recommended daily intake (RDA) for men aged over 19 is 400 micrograms, and the authors say that if other studies confirm their findings of the link between folate intake and aneuploidy, then a possible intervention would be to increase the RDA for men considering becoming fathers for at least three months before trying to conceive in order to reduce the risk of chromosomal abnormalities in their children.

Ms Suzanne Young, a researcher in Prof Eskenazi's group and the study co-ordinator, said: "Increasing folate intake can be as simple as taking a vitamin supplement with at least 400 micrograms of folate or eating breakfast cereal fortified with 100% of the RDA for folic acid. In addition, green leafy vegetables, such as spinach, can have up to 100 micrograms of folate per serving."

Disentangling the effects of folate from other micronutrients (e.g. the other vitamins) can be difficult, but the authors think they have succeeded in doing this by looking at several different nutrients in statistical analyses. Ms Young said: "The results of the different analyses were different, which gave us some confidence that we could look at the effect of these micronutrients separately. The definitive way to answer this question would be with a randomised control trial with folate supplementation."

Increasing Dairy Milk Production With Electrolyzed Drinking Water

2008-03-21T05:34:00.000-07:00

Many different approaches are being used to increase milk production of dairy cows. A study recently completed by researchers at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) indicates that improving drinking water through a technology created by EAU Technologies, has the potential to produce the desired results.

Penn Vet worked with EAU Technologies, Inc. (OTC Bulletin Board: EAUI), a leading provider of Electrolyzed Water - EMPOWERED WATER(TM) - for high- volume, business-to-business applications, for the controlled study. Dairy cows from Penn Vet's New Bolton Center campus were divided into two groups. One group's drinking water was electrolyzed, alkaline water and the control group was given regular well water. At the end of the 12-week test period, the Holstein cows showed an increase in milk production and an increase in milk fat content as well as a reduction in milk urea nitrogen (MUN).

"The electrolysis process improves the antioxidant and pH balance of the drinking water. The blood samples analyzed from the two groups indicates that the cows drinking the electrolyzed water showed differences in acid-base balance. We suspect that cows drinking the electrolyzed water had an increase in rumen activity and effectiveness; which in turn may explain the marked increased in milk butterfat," explained Dr. James Ferguson, Chief of Animal Production Systems, Department of Clinical Studies, New Bolton Center. "At the same time, the study indicated an increase in milk production for early lactating cows. The cows in the treated water group also drank more water and consumed about the same amount of feed. Bacterial Coliform levels within the EAU troughs also were significantly reduced."

The study is one of several EAU is conducting in a range of 30 to 3,000 herd dairies to measure the effectiveness of Empowered Water for milk production. As part of the Penn Vet study, in addition to the pH increase, EAU also developed a proprietary method of creating and controlling the level of measurable antioxidants in the water to better match the antioxidant conditions of a healthy cow's primary digestive system. And the EAU water also cleans the drinking water. Water samples collected from the troughs over the course of the study showed the EAU treated water was consistently negative for coliform organisms such as E. coli and other bacteria. Blood chemistry tests conducted also showed that blood urea nitrogen, creatinine, magnesium and chloride levels were lower in treated cows than those part of the control group.

"We know there are many factors that influence milk output and quality. By conducting tests in a variety of dairy settings, we believe we are gaining invaluable experience, application knowledge and acquiring accurate data to show that our Empowered Water(TM) can be an effective, natural solution, capable of impacting positive returns on milk and butterfat production. And, most importantly, benefit the overall health of the cow," added Wade Bradley, President and CEO of EAU Technologies. "This model directly mirrors EAU's business focus on providing our target industries, with high volume, robust and environmentally sound solutions."

The Penn Vet study is the first of the trial studies to be completed. Results will be published later this year. The remainder of the studies is expected to conclude over the next several months.

The increasing U.S. drug price crisis can be stopped and eventually reversed by separating drug discovery from drug marketing

2008-03-19T02:34:00.000-07:00

Stan Finkelstein, M.D., senior research scientist in MIT's Engineering Systems Division, and Peter Temin, Elisha Gray II Professor of Economics, present their research and detail their proposal in their new book, "Reasonable Rx: Solving the Drug Price Crisis," published by Financial Times Press.

Finkelstein and Temin address immediate national problems--the rising cost of available medicines, the high cost of innovation and the 'blockbuster' method of selecting drugs for development--and predict worsening new ones, unless bold steps are taken.

"Drug prices in the United States are higher than anywhere else in the world. Right now, the revenues from those drugs finance research and development of new drugs. We propose to reduce prices, not at the expense of innovation, but by changing the way innovation is financed," said Temin, also the author of "Taking Your Medicine: Drug Regulation in the US."

"Nationally, if we keep the current structure, in 50 years only hedge fund managers will be able to afford prescription drugs. Drug development will focus on therapies for those small groups of people who can pay a thousand dollars a pill. With income distribution widening and insurance carriers already refusing some coverage, this would be a disaster," said Temin.

"Prescription drugs have been left out of previous efforts to reform the delivery of health care. New initiatives to expand coverage must include a plan to reduce the high cost of drugs," Finkelstein added.

The book, which draws on the researchers' expertise in the realms of medicine and economics, proposes eliminating the linkage between drug prices and the cost of drug discovery while financing innovation and addressing the needs of society.

Their first bold step is conceptual, recognizing that we all have a critical stake in the products of pharmaceutical research.

Next, drawing on recent history, they propose dividing drug companies into drug discovery/development firms and drug marketing/distribution firms, just as electric utility firms were separated into generation and distribution companies in the 1990s.

Following the utility model, Finkelstein and Temin propose establishing an independent, public, non-profit Drug Development Corporation (DDC), which would act as an intermediary between the two new industry segments - just as the electric grid acts as an intermediary between energy generators and distributors.

The DDC also would serve as a mechanism for prioritizing drugs for development, noted Finkelstein.

"It is a two-level program in which scientists and other experts would recommend to decision-makers which kinds of drugs to fund the most. This would insulate development decisions from the political winds," he said.

Finkelstein and Temin's plan would also insulate drug development from the blockbuster mentality, which drives companies to invest in discovering a billion-dollar drug to offset their costs.

An example of the blockbuster mentality is developing a new drug for hypertension, one that varies only slightly from those already on the market, but that can bring in huge profits if aggressively marketed.

For Finkelstein, a physician, and Temin, an economist, societal needs for medicines are swiftly extending beyond national boundaries: Diseases affecting the developing world--afflicting people too poor to make drug development attractive for businesses--will soon affect health inside the United States.

"Global travel and climate change both require that U.S. drug development and innovation policy rethink the way drugs are developed, and for whom. Air travel, migrations, a global workforce-- all these mean unusual diseases could become usual here," Temin noted.

Climate change also may affect drugs their proposed DDC would select for funding.

"Especially in the southern states, tropical diseases are likely to increase with global warming, and people will need treatments for them. In our plan, the DDC would encourage research in advance of the market - and, we hope, in advance of disaster," he said.

Written by Sarah H. Wright, MIT News Office

http://www.mit.edu

About Generic ZANTAC - CVS, America's Largest Pharmacy Chain, Pays Nearly $37 Million to Settle Federal and State Generic Drug Switching Charges

2008-03-18T12:48:00.000-07:00

CHICAGO, March 18 /PRNewswire/ -- CVS Corporation, which claims to be America's largest pharmacy chain, has paid nearly $37 million to settle the nation's first retail pharmacy drug switching case. CVS allegedly charged the government up to 400 percent more for Medicaid patients by illegally changing generic Zantac(R) prescriptions from tablets to higher priced capsules, according to a multi-state complaint pursued by whistleblower attorneys Michael I. Behn and Linda Wyetzner.

The federal Complaint and Settlement Agreement unsealed today in the Northern District of Illinois stated that CVS garnered huge profits by evading federal and state price ceilings when it unlawfully switched dosage forms. Twenty-four states also entered separate settlements with the company, Behn and Wyetzner said.

The generic form of the antacid Zantac, ranitidine, typically comes in tablets. Given the drug's popularity, the government set maximum prices that Medicaid would pay for tablets, while infrequently prescribed ranitidine capsules had no maximum prices. When CVS switched patients' prescriptions from ranitidine tablets to the expensive capsules, it cost taxpayers up to 400 percent more, according to court documents.

This CVS case was pursued under federal and state False Claims Acts for more than five years by Illinois pharmacist Bernard Lisitza, the relator, and his Chicago attorneys, Behn and Wyetzner. "Bernie's your old-fashioned corner pharmacist who was alarmed by what he saw happening at CVS," said Behn. "It would have been easy for him to look the other way and let CVS's switching continue, at taxpayers' expense. Today's result is a vindication of a dedicated pharmacist's concern for his patients and all Americans who underwrite the costs of Medicaid."

The CVS case was spearheaded by "tough state prosecutors throughout the country," Behn added. "They stand ready, willing and able to take on big new cases. Lisa Madigan here in Illinois, Martha Coakley in Massachusetts, Marc Dann in Ohio, and other state Attorneys General have made health care fraud prosecutions a top priority, and this case is one of the results." Patrick Keenan, Deputy Attorney General of Illinois, Robert Patten and Peter Clark, Assistant Attorneys General of Massachusetts, and John Guthrie, Director of the Ohio Attorney General's Health Care Fraud Unit led the multi-state team, along with federal prosecutor Linda Wawzenski in Chicago.

The CVS $36.7 million settlement is another in a string of successful qui tam whistleblower cases brought by Behn & Wyetzner, Chartered. In 2006, Behn represented a pharmacist in a False Claims Act case against Omnicare for switching drug dosage forms which resulted in a settlement of more than $50 million. In 2005, Behn represented the plaintiffs in the largest whistleblower settlement in Illinois and the largest whistleblower settlement in Chicago, in which Northrop Grumman paid $134 million to resolve claims involving the B-2 "Stealth" bomber. Behn has also represented the American Association of Retired Persons ("AARP") before the Illinois Supreme Court in upholding the constitutionality of the Illinois False Claims Act.

End Of Agreements To Delay Market Entry Of Generic Medications Could Help Reduce Health Care Costs

2008-02-26T11:26:00.000-08:00

A "simple approach" to efforts to reduce health care costs that could "save consumers billions of dollars annually" is "stopping pharmaceutical companies from colluding with competitors to keep lower-cost generic alternatives to prescription drugs off the market," Jon Leibowitz, one of five members of the Federal Trade Commission, writes in a Washington Post opinion piece.

According to Leibowitz, the Hatch-Waxman Act, which Congress passed in 1984, has made "it easier for noninfringing generic drugs to enter the market, while giving brand-name manufacturers the patent protection they need to encourage the lifesaving research that is the hallmark" of the pharmaceutical industry.

However, the "crucial benefit is threatened by ... the emergence of 'pay-for-delay' settlements" -- in which brand-name pharmaceutical companies pay generic pharmaceutical companies to delay market entry of their products -- and the "willingness of some federal courts to permit such obviously anticompetitive agreements," Leibowitz writes. "When these troubling deals first came to light in the late 1990s, the FTC fought them -- and stopped them cold" -- as "no brand and generic companies entered pay-for-delay deals" between 2000 and 2004, but "that success is under siege," according to Leibowitz.

He writes that two federal appeals courts recently "have found that a brand-name drug company facing a patent challenge is free to pay any amount to keep a generic producer from entering the market until the patent expires." Leibowitz adds, "These rulings depart from the spirit of Hatch-Waxman and our nation's antitrust laws, and they harm consumers by subverting the competition at the heart of our free-market system."

He writes, "Not surprisingly, after two courts blessed such payoffs, the frequency of these settlements has increased sharply," adding, "In fiscal 2006, fully half of all pharmaceutical patent settlements (14 of 28) contained such payments." In response, FTC supports the "bipartisan legislation to ban such agreements that is moving through both houses of Congress" and, "until that law is enacted, we are doing everything in our power to end these unconscionable deals," Leibowitz concludes (Leibowitz, Washington Post, 2/25).

Pharmaceutical Companies Continue To Raise Prescription Drug Prices Despite Presidential Candidates' Criticism Of Industry

2008-02-24T13:55:00.000-08:00

The prices of brand-name medications have continued to increase despite calls from all three major presidential candidates for pharmaceutical companies to make their products more affordable, the Wall Street Journal reports. Wholesale prices for the 50 brand-name medications with the most sales increased by an average of 7.82% in 2007, compared with increases of 6.73% and 6.22% in the previous two years, according to Delta Marketing Dynamics. The overall U.S. economy had an inflation rate of 4.1% in 2007.

In some cases, pharmaceutical companies have increased the prices of brand-name medications scheduled to lose patent protection to prompt patients to switch to similar, newer products that will have patent protection for a number of years. William Little, president of Delta, said, "Companies are under great pressure to deliver revenue, and it's becoming increasingly difficult to do so as generics displace profitable brands."

However, such price increases could "backfire politically, pushing policies toward greater government power over price negotiations," according to the Journal. Presidential candidates Sens. John McCain (R-Ariz.), Barack Obama (D-Ill.) and Hillary Rodham Clinton (D-N.Y.) have criticized pharmaceutical companies over the high prices of the products and have announced proposals to address the issue.

McCain has said that he supports the legalization of prescription drug reimportation from Canada to reduce costs and "keep competition vigorous," and Obama on his Web site promises to "prevent (drug) companies from abusing their monopoly power through unjustified price increases." In addition, Clinton and Obama both have said that they support proposals to allow the federal government to negotiate prices directly with pharmaceutical companies under the Medicare prescription drug benefit.

According to some analysts, pharmaceutical companies have increased the prices of brand-name medications to "protect their margins in case the Medicare effort and others like it succeed," the Journal reports.

Comments
Jeff Nelligan, a spokesperson for CMS, said, "Allowing the government to negotiate drug prices would not generate additional savings" under the Medicare prescription drug benefit because the program "relies on health plans and their related pharmacy benefit managers to negotiate deep discounts with manufacturers."

Officials for the Pharmaceutical Research and Manufacturers of America said that the prices of brand-name medications "are determined by market transactions, and health plans are able to negotiate for discounts," adding that Medicare and Medicaid beneficiaries "have benefited from our competitive market approach."

Raymond James analyst John Ransom said, "Direct negotiations clearly could save the feds money, the concept being that the government makes almost 50% of purchases, and accordingly have almost fiat-like power to set their purchase price wherever they wish" (Won Tesoriero, Wall Street Journal, 2/21).

Heparin Chinese Supplier Was Never Checked By Chinese Drug Regulators

2008-02-16T23:55:00.000-08:00

Chagzhou Scientific Protein Laboratories, which own the factory that supplies Baxter's blood thinner, heparin, was never checked by drug regulators in China. The plant has no certification. Heparin has led to four recent deaths in the USA, as well as hundreds of allergic reactions throughout the country.

In fact, Dr. Murray Lumpkin, Deputy Commissioner for International Programs, FDA, says the Chinese authorities do not routinely inspect drug plants that make medications purely for exports to the USA. Chinese made drugs have been suspected of having caused serious adverse events and even death in some parts of the globe.

The US Food and Drug Administration (FDA) had not ordered a total recall of the shipped drug as it was feared this might provoke a serious national shortage. The Agency has suggested that health care professionals give their patients steroids or antihistamines in combination with heparin to prevent allergic reactions.

Baxter supplies half of the total US demand for heparin, a blood thinning drug made from pig intestines.

The Chinese factory, owned by Scientific Protein Laboratories, located outside Shanghai, produces and supplies the active ingredient for Baxter's heparin. The active ingredient is derived from an enzyme in pig intestines. Baxter processes, sterilizes and packages the finished product for distribution in the USA.

According to Lumpkin, Chinese drug regulatory authorities only inspect plants that manufacture medications for domestic sales. Although some plants that produce just for export are inspected, their inspections are not mandatory.

David Trunce, CEO, Scientific Protein Laboratories, said that their company cannot force Chinese authorities to come and inspect their plant. The company says it moved production to China three years ago because the country is the world's largest supplier of pigs.

Since December, 2007, US FDA and Chinese authorities (SFDA) have been working towards achieving better quality control procedures for drugs produced in China for the US market. Lumpkin said the FDA and SFDA have been working to develop a system whereby standards are met.

The US FDA would like to be able to make unannounced inspections of Chinese plants that supply the US market - surprise inspections. At present US FDA inspections in China are not surprise visits - the plant knows well in advance.

In 2007 the head of China's SFDA was executed for corruption - he was accused and convicted for taking backhanders (bribes) to approve drugs.

China has become the world's number one supplier of pharmaceutical active ingredients. As the country becomes more dominant in the supply of active ingredients to Western Europe, North America, and Japan, there is growing concern that regulatory standards have not kept up with this explosion in business. China has also entered a market which to date has been India's domain - the production of generic drugs.

New Technologies For Glaucoma Clinical Drug Trials

2008-02-16T23:54:00.000-08:00

The National Eye Institute (NEI) and the Food and Drug Administration (FDA) sponsored a symposium to consider new disease-relevant outcome measures appropriate for evaluating glaucoma therapies.

Currently, clinical drug trials for glaucoma therapies rely on standard perimetric criteria - i.e., a vision field test - as the primary functional outcome measure.

However, new technologies that assess abnormalities and changes in the optic nerve structure and its function offer vision researchers alternative pathways to better diagnose and treat glaucoma.

This symposium will focus on new outcome measures appropriate for evaluation of glaucoma therapies. The aim is to encourage the development of new glaucoma therapies, facilitate their evaluation and ultimately benefit patients.

Attendees included:

* Clinical researchers/basic scientists

* Clinical trialists

* Pharmaceutical company representatives

* Legal/advocacy firms

* Associations

* Biotech companies

Glaucoma facts

Glaucoma - a potentially blinding but treatable group of diseases - affects 2.2 million Americans age 40 and older, resulting in direct medical costs of $2.86 billion annually.

* Glaucoma robs individuals of peripheral and eventually central vision.

* Glaucoma is a complex group of neurodegenerative diseases that arises from progressive damage to the optic nerve and retinal ganglion cells and their axons.

* It is one of the four major aging eye diseases, alongside age-related macular degeneration, diabetic retinopathy and cataracts.

* About 50 percent of sufferers are unaware they have the disease.

* Glaucoma disproportionately affects minority populations: It is three times more common in African Americans than in whites and is the leading cause of irreversible vision loss in African Americans and Hispanics.

* There is a large public health burden from glaucoma due to decreased productivity, reduced independence and diminished quality of life.

Over-Use Of Anti-Inflammatory Drug May Lead To Complications

2008-02-04T03:30:00.001-08:00

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat arthritis, which affects one-third of all adults. These drugs are available in both prescription and over-the-counter (OTC) forms and are one of the most commonly prescribed medications in the world. Because of their widespread availability, patients may take both forms at the same time, either because of inadequate pain relief or because they are unaware that they are taking two drugs in the same therapeutic class. At the same time, health care providers may also be unaware that patients are taking more than one NSAID.

While it is well recognized that taking multiple NSAIDs can lead to gastrointestinal problems, it is not known whether there is a relationship between patients taking more than one NSAID and their health-related quality of life. A new study published in the February issue of Arthritis Care & Research found that taking two NSAIDs was associated with lower scores on a health-related quality of life assessment.

Led by Stacey H. Kovac of Durham VA Medical Center and Duke University, Durham, North Carolina, the study involved 138 patients from a large regional managed care organization who had filled at least one NSAID prescription between February and August 2002. Records of the prescriptions were captured from the pharmacy database and medical records. Participants also answered the 12-Item Short Form Health Survey, which evaluates health status and calculates a Physical Component Summary (PCS-12) and a Mental Component Summary.

The results showed that 26 percent of participants were dual users, meaning that they reported taking at least two NSAIDs (prescription, OTC, or both) during the previous month. Dual use was found to be associated with worse scores on the PCS-12 component of the health survey. The authors point out that little is known about patients who take multiple NSAIDs, whether prescription or OTC and that OTC use is difficult to track so few studies have evaluated it. The current study was able to include it by surveying patients via telephone. In addition, OTC medication is often not discussed during doctor visits, even though taking high doses of NSAIDs raises safety concerns. Physicians are advised to keep a complete list of a patient's medications and the authors note that doing so would help identify patients who are taking more than one NSAID. "The increased awareness may lead to better communication between the patient and provider about the appropriate use of NSAIDs," they state.

It may be that patients taking two NSAIDs sought pain relief due to inadequate clinical pain management, underscoring the need for health care professionals to be more aware of the importance of assessing and managing pain. Another possibility is that dual use could be an indicator for higher levels of pain. Although the study did not evaluate whether dual users were in greater pain, the authors suggest that research is needed on how to better educate patients to discuss their level of pain with their doctors and how to encourage health professions to question patients about their pain at each visit.

The authors note that future research should focus on establishing factors that cause dual NSAID use and evaluate the best methods of identifying patients taking two or more NSAIDs, who may be at a higher risk of adverse side effects due to the drugs. They conclude: "Adequate pain management may have the potential to reduce dual use, improve patient symptoms, including physical functioning, and reduce patient safety problems."

In Chronic Hepatitis C Silymarin Does Not Affect Virus Activity Or ALT Levels

2008-02-04T03:26:00.000-08:00

In a survey of patients with chronic hepatitis C who participated in a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored long-term treatment trial for patients who had failed to respond previously to antiviral therapy, approximately 40% acknowledged to interviewers at the time of enrollment that they were currently using or had in the recent past used herbal products for health purposes.

This information was somewhat surprising because these were patients with advanced liver disease who were clearly committed to conventional antiviral treatment for chronic hepatitis C, having been so treated previously, some on more than one occasion, but because they had failed to respond, were now willing to accept treatment again with pegylated interferon for another 3 and a half years. Among those who were or had used alternative therapies, silymarin (milk thistle) was the product of choice either on its own or together with other herbal products, representing 72% of all the herbals taken.

These findings are in the February issue of Hepatology, a journal published by Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article was also available online at Wiley Interscience.

These results do not come from a rigorous scientific study because the products used were self-administered by the patients who entered the trial and no information was obtained on the duration or dose of the herbal taken. Still, in comparing users with non-users, while no difference was found for blood ALT or HCV levels between the two groups, the herbal users did report somewhat fewer symptoms and a better quality of life.

The current recommended treatment for patients with HCV infection is combination therapy with pegylated interferon and ribavirin. However, it leads to a sustained virological response in only a third to a half of all patients with the predominant form of the infection in the U.S., namely genotype 1, and it can cause unpleasant and sometimes serious side effects. The NIH study, referred to as the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial, was designed, therefore, to treat persons with advanced chronic hepatitis C who had failed previous antiviral therapy with the hope that the long-term treatment would reduce progression of the chronic liver disease even if it did not affect the virus itself. The reason for interviewing enrollees in the trial was to determine the extent of use of alternative therapies in this committed group, since the popularity of herbal products has increased in the U.S., many HCV patients choosing to supplement, or even replace, the standard treatment with herbals. Silymarin (milk thistle extract) has been the most popular option for people with liver disease. Although it is the most frequent product utilized, silymarin has not been rigorously studied using accepted scientific approaches, and therefore such studies are clearly required and warranted.

For the present survey, researchers interviewed all HALT-C participants on past and current use of all prescription and non-prescription drugs, including herbal medications, dietary supplements and other botanical products. Of 1145 study participants, 56 percent said that they had never used herbal products, while 23 percent were using them currently, some 60 different varieties. Silymarin was by far the most common. Usage was higher among men, among non-Hispanic whites, and among the more highly educated. Interestingly, the researchers also found geographic disparities in silymarin usage. It was most popular in Colorado, Michigan and Southern California and least popular in Maryland and Massachusetts.

In comparing the clinical data of silymarin users and non-users, the researchers found that "the levels of HCV RNA were not significantly different between silymarin users and non-users," indicating no effect on virus activity. Similarly, the product did not alter serum ALT levels, indicating no effect on hepatic inflammation. However, after adjusting for covariates, the data showed that silymarin users reported less fatigue, nausea, liver pain, anorexia, muscle and joint pain and better general health than non-users.

The better scores in a small number of symptoms among silymarin users compared to non-users are insufficient to support the value of this alternative therapy, the authors conclude. Compelling information can come only if a scientifically valid study is performed. "Currently in progress, therefore, is a properly designed prospective, randomized, controlled trial in which a fully characterized, purified and standardized silymarin formulation is being evaluated," they report.

No Reduction In Risk Of Heart Attack Or Stroke When Ezetimibe Is Used Alone Or With Statins (Vytorin)

2008-02-01T13:28:00.000-08:00

On January 14, 2008, Merck/Schering Plough Pharmaceuticals issued a Press Release reporting preliminary results from the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial. This trial was designed to evaluate the amount of atherosclerotic plaque in blood vessels located in the neck based on images obtained through ultrasound in patients treated with Vytorin (ezetimibe plus simvastatin) or simvastatin alone. Merck/Schering Plough Pharmaceuticals, the company that conducted the trial, stated that there was no significant difference between Vytorin and simvastatin in the amount of atherosclerotic plaque in the inner walls of the carotid (neck) arteries despite greater lowering of LDL-cholesterol (bad cholesterol) with Vytorin compared to simvastatin. FDA has not received a final study report and at this time it is not clear why the lower levels of LDL cholesterol in the patients who took Vytorin did not lead to lesser amounts of plaque compared to patients treated with simvastatin alone.

ENHANCE was a 2-year, multi-national, randomized, double-blind study conducted in 720 patients with heterozygous familial hypercholesterolemia (HeFH), a condition that is associated with very high cholesterol levels and affects approximately 0.2 percent of the population. Half of the patients were treated with 10 mg of ezetimibe combined with 80 mg of simvastatin and half with 80 mg of simvastatin alone.

An elevated LDL-cholesterol level is an established risk factor for heart disease and many studies have supported the conclusion that lowering cholesterol levels reduces the risk for heart attack and stroke. Ezetimibe inhibits the absorption of cholesterol in the intestine and is approved to lower LDL-cholesterol levels. Simvastatin (Zocor) is a lipid-lowering agent (“statin”) approved to reduce LDL and increase high-density lipoprotein (HDL) (good) cholesterol levels and reduce the risk of cardiovascular events such as heart attack and stroke. Vytorin is approved for reducing LDL and increasing HDL cholesterol levels.

There are no clinical studies available that demonstrate a reduction in risk of heart attack or stroke when ezetimibe is used alone or in combination with a statin, including the fixed-dosed combination drug of ezetimibe and simvastatin, Vytorin. While the overall incidence of cardiovascular events in ENHANCE was similar in both the ezetimibe/simvastatin and simvastatin-alone groups, there were not enough patients in this study to reliably test whether treatment with ezetimibe/simvastatin compared with simvastatin alone reduces the risk of cardiovascular events. An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining this question in 12,500 patients and will likely be completed in 2011. Physicians and patients should carefully consider the available data and current labeling for Zetia and Vytorin as they make individual treatment decisions.

This early communication is in keeping with FDA’s commitment to inform the public about ongoing postmarketing drug issues. Once Merck/Schering Plough Pharmaceuticals completes the analysis of the unblinded data from ENHANCE, it will submit a final study report to FDA. Once FDA receives the final study report, FDA estimates it will take approximately 6 months to fully evaluate the data. After reviewing the data from the ENHANCE study, and considering all other available information about the link between LDL lowering and reduction of cardiovascular events, FDA will determine whether any further regulatory action is warranted with regard to Zetia and Vytorin and also whether any changes to FDA’s current approach to drugs that lower LDL cholesterol are warranted.

Patients should talk to their doctors if they have any questions about the information from the ENHANCE trial.

The FDA urges both healthcare professionals and patients to report side effects from the use of ezetimibe to the FDA's MedWatch Adverse Event Reporting program

Potential Range Of Drugs That Are Cheaper And More Available Following Pharmaceutical Breakthrough

2008-02-01T13:23:00.000-08:00

A new study published in the February 2008 print edition of The FASEB Journal (http://www.fasebj.org/) describes a scientific advance that should reduce the cost and increase the availability of a wide range of drugs. In the report, University of Pennsylvania researchers describe how they used gene therapy to reduce the time it takes to breed large animals capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. This represents a significant milestone in drug development, as current methods involve cloning, which takes more time and generally costs more.

"Having an easier way to harness nature's power to produce large quantities of specific proteins in milk could increase the availability of drugs for people who could otherwise not afford these treatments," said Ina Dobrinski, one of the researchers on the study.

The study also is significant because it may also be a new way to eliminate diseases in future generations of animals, such as those used for livestock. Here's why: To get the goats to produce specific proteins, the researchers used radiation to kill a portion of a male goat's germ cells (the cells that produce sperm). Then they used a modified adeno-associated virus (a well studied and tolerated gene therapy vector) to insert a gene in the remaining cells. Once the new gene took hold in the germ cells, a predictable number of female offspring produced the desired protein in their milk. The advance is immediately valuable for pharmaceutical development and biology research, but a similar approach could be used to bolster the food supply by eliminating genetic disorders in animals over several generations. It is also possible that once perfected, this technique could eliminate disease genes in humans over several generations, assuming ethical concerns can be resolved adequately.

"For thousands of years, people have domesticated cows and goats to make milk, butter and cheese. And for thousands of years dairy products have been used as folk remedies for practically every human illness. Most have been completely ineffective." said Gerald Weissmann, MD, editor-in-chief of The FASEB Journal. "So it is reassuring that modern science would find a way to use the milk we drink to yield of drugs that actually work."

Wild-type KRAS Colorectal Tumours Respond To Panitumumab

2008-02-01T13:18:00.000-08:00

Patients with colorectal tumours expressing the wild-type KRAS gene show significantly increased progression free survival with panitumumab (Vectibix), a monoclonal antibody targeting EGFR, while those with mutations in KRAS do not, according to data from a phase 3 trial reported at the 2008 Gastrointestinal Cancers Symposium this week (25-27 January, Orlando, Florida).

The study assessed KRAS status - a gene coding for a protein involved in signalling cell division - in tumour samples from 427 patients with metastatic colorectal cancer taking part in a phase 3 trial in which they were randomised to panitumumab (6.0mg/kg every two weeks) plus best supportive care or best supportive care alone. Results reported at the meeting showed that 43% of these patients had KRAS mutations.

Patients with tumours expressing wild-type KRAS showed a 55% increase in progression free survival when treated with panitumumab compared to those given best supportive care without the antibody (hazard ratio 0.45; 95% confidence interval 0.34-0.59). In contrast, those with mutant KRAS showed no response (HR 0.99; 95% CI, 0.73-1.36) (p<0.0001). The median progression free survival was significantly longer, at 12.3 weeks, in patients with wild type KRAS treated with panitumumab than those with mutant KRAS (7.4 weeks). This compared with 7.3 weeks in both KRAS groups treated with best supportive care.

In the group of patients treated with panitumumab, 17% of those with wild type KRAS expressing tumours responded and 34% had stable disease, while 0% of those with mutant KRAS responded and 12% had stable disease.

Reporting the results, Rafael Amado, executive director, oncology, Amgen Inc, Thousand Oaks, California, USA, said: "In patients with chemotherapy-refractory metastatic colorectal cancer, the clinical efficacy of panitumumab monotherapy appears to be restricted to patients with wild type KRAS tumours." He added: "KRAS genotyping of tumours should be strongly considered in patients being treated with panitumumab monotherapy."

Panitumumab is currently approved in Europe as monotherapy for the treatment of patients with EGFR expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS, and after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

[2008 Gastrointestinal Cancers Symposium. Abstract 278]

Suicide Risk Of Antiepileptic Drugs

2008-02-01T13:02:00.001-08:00

The US Food and Drug Administration (FDA) issued new information, yesterday, 31st January, to alert doctors and other health professionals about the increased risk of patients having suicidal thoughts and behaviours as a result of taking antiepileptic drugs for epilepsy, bipolar disorder, migraines, and other conditions.

The agency has just completed a review of placebo controlled studies on 11 antiepileptic drugs and found that patients who took them had two times the risk of suicidal thoughts and behaviours (suicidality) of patients who took placebo only (0.43 versus 0.22 per cent). In epidemiological terms, this is an extra 2.1 per 1,000 patients.

In March 2005, the FDA asked manufacturers of marketed antiepileptic drugs for which there were adequately designed controlled clinical trials, for the data following a preliminary analysis of several drugs that suggested an increased risk of suicidality. The agency received and analysed data from 199 such trials covering 11 drugs.

The analysis covered 27,863 patients on the drugs, and 16,029 on placebo. Among the patients taking the drugs there were 4 suicides and 105 reports of suicidal thoughts and behaviours. Among the placebo patients, there were no suicides and 35 reports of suicidal thoughts and behaviours.

The risk of suicidality was observed to increase after one week of starting on the drugs, and stayed higher for at least 24 weeks.

There was no clear pattern of risk across age groups, and the risk was the same for all 11 drugs and all demographic subgroups, said the agency.

Director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, Dr Russell Katz said:

"We want health care professionals to have the most up to date drug safety information."

" This is an example of FDA working with drug manufacturers throughout products' lifecycles to keep health care professionals informed of new safety data," he added.

The agency advises patients who are presently on antiepileptic medication not to change or stop their dose until they have discussed the impact of this information with their doctor.

Doctors and other health care providers should contact their patients, their patients' caregivers and families and let them know about the increased risk of suicidal thoughts and behaviours so they can look out for any changes in behaviour.

The full list of drugs covered by the FDA analysis is shown below. Note that some of them are also available in generic form.

The FDA said that although they only analysed these drugs, they fully expected the increased risk of suicidality to be present in all antiepileptic drugs, including those not shown here.

Drug Brand Name(s)
Carbamazepine Carbatrol, Equetro, Tegretol, Tegretol XR
Felbamate Felbatol
Gabapentin Neurontin
Lamotrigine Lamictal
Levetiracetam Keppra
Oxcarbazepine Trileptal
Pregabalin Lyrica
Tiagabine Gabitril
Topiramate Topamax
Valproate Depakote, Depakote ER, Depakene, Depacon
Zonisamide Zonegran

The FDA said they were now working with the drug companies to ensure this new information is included in the product label and accompanying patient and doctor information sheets. They are expecting the information to apply to all antiepileptic drugs and not just the ones given here.

Healthcare professionals who prescribe antiepileptic drugs should:

* Balance the risk for suicidality with the clinical need for the drug
* Be aware of the possibility of the emergence or worsening of depression, suicidality, or any unusual changes in behavior;
* Inform patients, their families, and caregivers of the potential for an increase in the risk of suicidality so they are aware and able to notify their healthcare provider of any unusual behavioral changes.

Information for patients, family members, and caregivers:

* Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
* Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
* Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
* Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
o Talking or thinking about wanting to hurt yourself or end your life
o Withdrawing from friends and family
o Becoming depressed or having your depression get worse
o Becoming preoccupied with death and dying
o Giving away prized possessions

If these or any new and worrisome behaviors occur, contact the responsible healthcare professional immediately.

Background and Data Summary

After preliminary analyses of data from several drugs in this class suggested an increased risk of suicidality, in March 2005, FDA requested data from manufacturers of marketed antiepileptic drugs for which there were adequately designed controlled clinical trials in order to review the possible association between these drugs and suicidality events. In an effort to obtain the most complete and accurate data for this review, requests for additional information and clarification were sent to the manufacturers in 2006 and 2007. The analyses performed were similar to those performed by FDA for antidepressant drugs in the last several years.

One-hundred ninety nine placebo-controlled clinical studies covering eleven different drugs were included in the primary analysis. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes. The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups. Patients included in the analysis were five years of age or older. The individual sponsors of the drugs were responsible for identifying suicidal behavior and suicidal ideation events in their databases based on the instructions provided by FDA.

There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups. Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups (See Table). In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders (See Table). The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks. The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups.

Promising Drugs For Non-Hodgkin's Lymphoma May Change European Market Dynamics

2008-01-30T02:44:00.001-08:00

The European non-Hodgkin's lymphoma (NHL) therapeutics market has been monopolised by MabThera for a number of years. Although CHOP chemotherapy is the major treatment for all forms of NHL, it is highly genericised with limited prospects for revenue growth. However, market dynamics are poised to change in the near future due to the anticipated launch of many promising pipeline drugs currently in phase 3 of their development.

New analysis from growth consulting company Frost & Sullivan (http://www.pharma.frost.com), European Non-Hodgkin's Lymphoma Therapeutics Markets, finds that the market earned revenues of USD 2.2 billion in 2006 and estimates this to reach USD 7.2 billion in 2013.

"The relapsing nature of NHL is creating the need for new therapeutic options," notes Frost & Sullivan Research Analyst Ranjith Gopinathan. "Though MabThera is very popular and has gained widespread acceptance, there still exists a high unmet need among NHL patients."

About 1.75 million people worldwide are living with NHL. As the risk of developing the disease increases with age, the rising life expectancy across Europe is leading to a growing demand for treatments.

MabThera is projected to retain its market leadership position over the next 5-6 years. Most drugs in the pipeline are being positioned as add-on combination therapies with MabThera or CHOP. The market is poised to accelerate from 2012 onwards, pushed by several promising drugs, currently in their phase 3 development stage.

"Add-on drugs, in combination with MabThera or chemotherapy, are a prospective market driver," states Gopinathan. "For instance, Favrille expects Favid to be a blockbuster when approved for commercialisation."

Most research-based biotechnology firms are however currently facing considerable losses. Moreover, stringent clinical and regulatory hurdles could curb potential returns from biotechnology products. For such companies, difficulties in securing resources to fund clinical trials will delay the development process and extend the time to market.

Companies such as Favrille and Genitope are facing mounting operating expenses due to high investments in research. Any regulatory setback could jeopardise their business sustainability.

Additionally, most oncologists are satisfied with MabThera and may not feel the need to replace it entirely with new drugs. Hence, combination drugs with MabThera or CHOP would gain easier acceptance among oncologists and patients.

"Big pharma should look for strategic alliances or acquisition of promising pipeline drugs," advises Gopinathan. "Small-sized biotechnology companies should focus on research and finding a suitable marketing partner."

European Non-Hodgkin's Lymphoma Therapeutics Markets is part of the Pharmaceutical & Biotechnology Growth Partnership Service Programme, which also includes research in the following markets: European Urinary Incontinence Therapeutics Markets, European Endometriosis Therapeutics Markets, Blockbusters Going Off-patent: Opportunities for Generics Manufacturers in Europe, European Osteoarthritis Market, European Head and Neck Cancer Therapeutics Markets and European Breast Cancer Therapeutics Markets. All research included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants. Interviews with the press are available.

Picoplatin Safety Data In Colorectal Cancer

2008-01-28T02:54:00.000-08:00

Poniard Pharmaceuticals, Inc. (Nasdaq: PARD), a biopharmaceutical company focused on oncology, announced that it has presented safety data from a Phase 1 dose-escalation study of picoplatin, the Company's lead product candidate, at the 2008 Gastrointestinal Cancers Symposium, a meeting of the American Society of Clinical Oncology (ASCO) which is being held in Orlando, Fla.

The poster presentation included safety data from a Phase 1 study of picoplatin in combination with 5-fluorouracil (5FU) and leucovorin (LV) as a first-line treatment for metastatic colorectal cancer (mCRC). The Phase 1 study seeks to establish the maximum tolerated dose of picoplatin and provide information on the safety of picoplatin when combined with 5FU and LV for the treatment of colorectal cancer. Promising safety data observed from the study to date formed the basis for further development of picoplatin in our ongoing Phase 2 trial in mCRC.

"These study results suggest that picoplatin does not cause severe neurotoxicity, as is commonly seen in mCRC patients treated with the regimen of 5FU and LV with oxaliplatin," said Jerry McMahon, Ph.D., chairman and CEO of Poniard Pharmaceuticals. "Picoplatin has demonstrated both good tolerability and no severe neuropathies when combined with 5FU and LV. We believe picoplatin has the potential to be a preferred platinum for the treatment of colorectal and other cancer indications."

Current National Comprehensive Cancer Network (NCCN) guidelines encourage the discontinuation of FOLFOX (5FU and LV with oxaliplatin) after three months of therapy or sooner if significant (Grade 3 or greater) neurotoxicity develops. For more information, please see http://www.nccn.org.

In the Phase 1 study, 50 patients were treated with picoplatin on either an every-two-week or an every-four-week basis in combination with the standard of care every-two-week dose of 5FU and LV. Patients received up to 28 cycles, and the therapy was well tolerated. Increased hematological toxicity was observed at higher doses. None of the patients treated with picoplatin exhibited a Grade 3 or higher neuropathy and only 9 of 45 patients (20 percent) experienced mild neuropathy. No neuropathy of Grade 2 or greater was observed in the 26 patients who received greater than or equal to 400 mg/m squared picoplatin. Mild nephro- and oto- toxicity were observed infrequently. The dose limiting toxicity (DLT) was most frequently hematological with neutropenia and thrombocytopenia. The maximum tolerated dose was established in the every-four-week schedule at 150 mg/m squared. The maximum tolerated dose for the every-two-week schedule has not yet been reached.

Based on the evidence of a more attractive safety profile of picoplatin in this combination (FOLPI) compared to the standard of care regimen with oxaliplatin (FOLFOX) as well as clinical activity in the Phase 1 study, the Company initiated a randomized Phase 2 trial in November, 2007 to evaluate intravenous picoplatin in the first-line treatment of mCRC. The Phase 2 trial is intended to generate proof-of-concept data to further evaluate efficacy and safety, including neuropathy of picoplatin in combination with 5-FU and LV (FOLPI versus FOLFOX) and to provide support for a potential registrational Phase 3 trial. The Company expects to present data from the Phase 1 and 2 mCRC program in scientific forums around mid year.

About Picoplatin

Picoplatin is an intravenous chemotherapeutic agent that has an improved safety profile compared to existing platinum-based chemotherapeutics. It was designed to overcome platinum resistance associated with the treatment of solid tumors. Picoplatin has been evaluated in more than 750 patients and has demonstrated activity in multiple indications with no evidence of significant kidney, nerve toxicity or hearing loss, toxicities commonly observed with other platinum chemotherapy drugs.

In addition to the Phase 2 clinical trial in patients with mCRC, Poniard is evaluating intravenous picoplatin in an ongoing pivotal Phase 3 trial, known as SPEAR (Study of Picoplatin Efficacy After Relapse), in small cell lung cancer. This registrational trial is being conducted under a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA) and is evaluating overall survival as the primary endpoint. The Company also is evaluating intravenous picoplatin in an ongoing Phase 2 clinical trial for the treatment of hormone refractory prostate cancer (HRPC). Oral picoplatin is being evaluated in a Phase 1 clinical trial in solid tumors.

About Poniard Pharmaceuticals

Poniard Pharmaceuticals, Inc. is a biopharmaceutical company focused on the development and commercialization of innovative oncology products to impact the lives of people with cancer. Picoplatin, the Company's lead platform product candidate, is a new generation platinum therapy with an improved safety profile. Picoplatin is designed to overcome and prevent platinum resistance associated with chemotherapy in solid tumors, and is being studied in multiple cancer indications, combinations and formulations. Clinical trials of intravenous picoplatin include a Phase 3 trial in small cell lung cancer and Phase 2 trials in metastatic colorectal and hormone- refractory prostate cancer, as well as a clinical trial of oral picoplatin in solid tumors. Picoplatin has not been approved by regulatory authority for use in humans. For additional information please visit http://www.poniard.com.

This release contains forward-looking statements, including statements regarding the Company's business objectives and strategic goals, drug development plans, results of clinical trials and the potential safety and efficacy of its products in development. The Company's actual results may differ materially from those indicated in these forward-looking statements based on a number of factors, including risks and uncertainties associated with the Company's research and development activities; the results of pre- clinical and clinical testing; the receipt and timing of required regulatory approvals; the market's acceptance of the Company's proposed products; the Company's anticipated operating losses, need for future capital and ability to obtain future funding; competition from third parties; the Company's ability to preserve and protect intellectual property rights; the Company's dependence on third-party manufacturers and suppliers; the Company's lack of sales and marketing experience; the Company's ability to attract and retain key personnel; changes in technology, government regulation and general market conditions; and the risks and uncertainties described in the Company's current and periodic reports filed with the Securities and Exchange Commission, including the Company's Annual Report on Form 10-K for the year ended December 31, 2006, as amended, and most current Quarterly Report on Form 10-Q. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. The Company undertakes no obligation to update any forward-looking statement to reflect new information, events or circumstances after the date of this release or to reflect the occurrence of unanticipated events.

European Medicines Agency Recommends Apprval Of Novel Oral Anticoagulant, Dabigatran Etexilate - Pradaxa (R)

2008-01-28T02:40:00.000-08:00

Boehringer Ingelheim announced that the Committee for Medicinal Products in Human Use (CHMP) of the European Medicines Agency has issued a positive opinion to recommend marketing authorisation of their novel, oral direct thrombin inhibitor, dabigatran etexilate. The CHMP recommends approval of dabigatran etexilate for the prevention of venous thromboembolic events in patients who have undergone total hip replacement surgery or total knee replacement surgery.

The positive opinion is a recommendation to the European Commission that authorization to market the drug should be granted in the European Union which normally occurs within 67 days. Dabigatran etexilate will be marketed by Boehringer Ingelheim exclusively under the brand name Pradaxa®, with a planned launch in all 27 countries of the European Union.

Dr Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine said "We welcome the positive opinion of the EMEA which is the first recommendation for approval by a regulatory authority for our novel oral anticoagulant drug Pradaxa®. This announcement represents a major milestone in the advancement of anticoagulation therapy for thromboembolic diseases. We are pleased that our new oral thrombin inhibitor offers the potential for physicians to ensure that patients in need receive effective and safe thromboprophylaxis."

Patients who have undergone total hip or knee replacement are at high risk of venous thromboembolism (VTE). This risk extends beyond the usual period of hospitalisation, as thromboprophylaxis treatment is often discontinued following discharge due to the complex administration of current anticoagulants.2 As dabigatran etexilate is given as a fixed oral dose, it can be administered conveniently both in and out of the hospital setting, providing patients with effective protection from potentially dangerous thrombi (blood clots).

Dabigatran etexilate has a rapid onset and offset of action and predictable anticoagulation effect, without the need for coagulation monitoring. It specifically and reversibly inhibits thrombin, the central and essential enzyme in the coagulation cascade responsible for thrombus formation. Dabigatran etexilate exhibits no drug-food interactions and has a low potential for drug-drug interactions.3,4

Clinical data from the RE-NOVATETM and RE-MODELTM trials were included in the submission to European authorities in February 2007 for the first intended license indication for dabigatran etexilate. Oral, once daily administration of both 150 or 220 mg dabigatran etexilate was demonstrated to be as effective and safe as injectable enoxaparin (40mg) in preventing VTE and all cause mortality following total hip replacement surgery and following total knee replacement surgery in the RE-NOVATETM and RE-MODELTM trials respectively.5,6 All test results were evaluated by a central adjudication committee that was blinded to the treatment received by any patient.

Anticoagulation-related bleeding is the primary safety concern during hip or knee replacement surgery, since major bleeding into the replaced joint can have a detrimental impact on clinical outcome.5 In both trials, few major bleeding events (including those occurring at the surgical site) were reported and incidence did not differ significantly between dabigatran etexilate and enoxaparin treatment groups (during the RE-NOVATETM trial, major bleeding events occurred at 2.0% and 1.3% for dabigatran etexilate 220 mg and 150mg groups versus 1.6% for enoxaparin and during the RE-MODELTM trial, major bleeding events occurred at 1.5% and 1.3% for dabigatran etexilate 220 mg and 150mg groups versus 1.3% for enoxaparin).5,6

In all phase III trials reported to date, patients were frequently monitored and assessed for liver enzyme elevations by an independent data safety monitoring committee. Liver enzyme aminotransferase (ALT) elevations greater than three time the upper limit of normal (ULN) were low throughout the entire treatment periods with dabigatran etexilate and did not differ significantly between the treatment groups.

Similarly, the incidence of acute coronary events was low, particularly in the three month follow up period, with no significant differences between all treatment groups.

Boehringer Ingelheim continues to evaluate the efficacy and safety of dabigatran etexilate in a range of thromboembolic disease conditions. RE-VOLUTION™ is an extensive clinical trial programme involving more than 34,000 patients worldwide. Recent progress announcements include the early enrolment completion of 18,114 patients in the landmark RE-LY™ trial to evaluate the efficacy and safety of dabigatran etexilate for stroke prevention in patients with atrial fibrillation. Other ongoing studies are evaluating the efficacy and safety of dabigatran etexilate in the treatment of acute VTE, the secondary prevention of VTE and acute coronary syndromes.

Design, Production Of Extremely Novel Drugs Enabled By New Method

2008-01-27T02:02:00.000-08:00

A new chemical synthesis method based on a catalyst worth many times the price of gold and providing a far more efficient and economical method than traditional ones for designing and manufacturing extremely novel pharmaceutical compounds is described by its University at Buffalo developers in a review article in the current issue of Nature.

The chemistry, the basis of a new biotech startup company called Dirhodium Technologies, LLC in Buffalo, has the potential to improve dramatically the design and production of new drugs based on small molecule organic compounds, which comprise the great majority of new drug applications.

"If you tend to make things by methods that have been around for 100 years, there's a decent chance that you'll make something that's already known or is very close to something that is," said Huw M.L. Davies, Ph.D., UB Distinguished Professor in the Department of Chemistry and lead author on the Nature paper. "But if you use an entirely new strategy like the one we developed, virtually every reaction you run will result in a new structural entity. That's critical to drug development."

The chemical strategy Davies developed depends on the use of proprietary catalysts his company manufactures.

Minute amounts of the rhodium-based catalyst can have a major impact, he explained, with 1 gram capable of producing 10 kilograms of a pharmaceutical product.

"So it's like a bit of 'golden dust' to get everything going," said Davies, a researcher at UB's New York State Center of Excellence in Bioinformatics and Life Sciences and president and chief executive officer of Dirhodium Technologies.

"As rhodium metal costs 10 times the price of gold, the catalyst is a high-value material," he said.

Available through chemical supply companies, the reagents are being used by pharmaceutical scientists in both industry and academia.

Already, one major pharmaceutical company is using the reagents to synthesize a compound now in clinical trials.

"Demand for our catalysts has gone from gram to kilogram quantities, from fractions of an ounce to multiple pounds," said Davies.

So far, the new synthesis strategy has generated compounds that have potential activity against a broad range of disease states, from cancer to central nervous system disorders, such as depression, to inflammatory and microbial diseases and medications for treating cocaine addiction.

"This method is like an enabling technology, making available new targets and materials that previously were out of range," said Davies.

Its ability to result in never-before-seen chemical structures is making Davies' collaborations with scientists in partner institutions on the Buffalo Niagara Medical Campus especially fruitful.

"We're using this as a platform for drug discovery, collaborating through the Center of Excellence with biologists at UB, Roswell Park and Hauptman Woodward Medical Research Institute," said Davies.

Davies' company is one of 10 life sciences spinoffs based in the Center of Excellence, which has the dual mission of promoting life sciences research while facilitating economic development in Upstate New York.

In addition to helping drug companies design novel leads for new products, the new chemistry also allows pharmaceutical companies to synthesize efficiently and economically large quantities of novel compounds.

Through catalysis, the chemical synthesis method the UB researchers developed allows for highly unusual functionalizations of carbon-hydrogen bonds, Davies explained.

"The method allows you to transform a molecule from a simple structure to a much more elaborate, drug-like material," he said, "so it goes from a cheap building block to a potential drug-like candidate. Without a catalyst, it won't happen."

A major advantage of Davies' chemical strategy is that the resulting compounds are produced selectively as single mirror images.

Pharmaceutical companies prefer to develop new chiral drugs (chiral meaning "handed") as a single isomer because opposite mirror images can have different biological effects and may be harmful.

"A small amount of our catalyst can be used to generate large amounts of the active mirror image of the pharmaceutical ingredient," Davies said.
----------------------------

The UB research has been funded by the National Institutes of Health and the National Science Foundation, both of which were recently renewed for a total of $1.6 million. The work also has been supported by the UB Center for Advanced Biomedical and Bioengineering Technology (UB CAT), located in the Center of Excellence.

The Nature paper was co-authored by James R. Manning, a graduate student in the Department of Chemistry in the UB College of Arts and Sciences.

The New York State Center of Excellence in Bioinformatics and Life Sciences was created in Buffalo in 2002 as part of more than $200 million dollars in investment from state, federal, industrial and philanthropic sources to create a hub of life sciences expertise and innovation in Upstate New York. The COE brings a strong foundation in life sciences research and discovery to its mission and collaborative efforts with industry, government and researchers around the world to improve the health and well-being of the population. The Center of Excellence is a major UB research center; its research partners are Roswell Park Cancer Institute and Hauptman-Woodward Medical Research Institute.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

Source: Ellen Goldbaum
University at Buffalo