FDA Needs Larger Budget, Agency Science Board Says

FDA needs an expanded budget of about $375 million in fiscal year 2009 to reverse longtime funding shortfalls, the agency's Science Board subcommittee said on Tuesday, CongressDaily reports. The subcommittee estimated that FDA needs an additional $2.2 billion over five years to bring the agency's funding level to $3.7 billion by FY 2013. In addition, the subcommittee recommended that FDA receive an additional $128 million in food safety funding in FY 2009 and $750 million over five years. President Bush in his proposed budget requested $51 million in additional agency funding, which would bringing total funding to $1.7 billion, with $42 million dedicated to food safety.

House Energy and Commerce Committee Chair John Dingell (D-Mich.) said, "These estimates show that the president's budget has completely missed the mark in terms of what is truly needed to protect Americans," noting that the science board recommendations are seven times Bush's proposed levels (Edney, CongressDaily, 2/27).

In related news, FDA Commissioner Andrew von Eschenbach -- "in an unusual public departure from Bush administration policy" -- said in an interview that he had requested a greater funding increase for the agency than was present in Bush's budget plan. Von Eschenbach also said that the agency needs better organization to oversee drug safety and other issues more effectively. He said, "I think to do what we need to do requires substantially more dollars than what has been invested in the FDA thus far," adding that "there are issues that this agency needs to have addressed and that it's going to have to be transformed" (Wilde Mathews, Wall Street Journal, 2/27).

Postmarket Oversight
Meanwhile, FDA on Tuesday announced a proposal that aims to improve postmarket oversight of prescription drugs, the Wall Street Journal reports. Announced in an e-mail to employees, the "Safety First" plan will create a new database to list the potential side effects of prescription drugs and provide a schedule for following up on questions. The agency also will revise its procedure for making certain regulatory decisions, "particularly those based on emerging safety worries, though the new moves don't go as far as some critics have advocated," according to the Journal. The plan gives new authority to the Office of Surveillance and Epidemiology, stopping "short of divorcing the two functions" of the office, which is to approve drugs and monitor for safety issues after approval, the Journal reports.

Under the plan, the office will:

* Implement multidisciplinary groups, including the premarket approval group and the safety office, to work together to make decisions and allow the groups to make appeals to higher-level officials in instances of disagreement;

* Appoint new, dedicated officials who will be responsible for focusing on safety in each of the divisions;

* Have primary authority to approve drug brand names and labeling; and

* Have the authority to commission certain kinds of research, including requiring drug makers to conduct studies.

The office will not have the authority to approve label changes and to remove a prescription drug from the market. Von Eschenbach said, "What we're doing is to create an integrated approach ... that isn't going to perpetuate problems of the past but really try to embrace what have to be solutions of the future."

In the future, FDA will implement a second phase of the plan, called Safe Use, which will focus on the safety of prescription drugs in real-world settings. However, there are few details available on that plan as of yet, according to an agency official (Wilde Mathews, Wall Street Journal, 2/26).

Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock

Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.

Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 µg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 µg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.

Results A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).

Conclusions Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors.

Discussion

In this multicenter, randomized, double-blind trial of low-dose vasopressin as compared with norepinephrine in patients with septic shock, we were not able to demonstrate any significant difference in the 28-day mortality rate (35.4% in the vasopressin group vs. 39.3% in the norepinephrine group, P=0.26). We were also unable to demonstrate any significant difference between the two study groups in 90-day mortality or the rate of organ dysfunction. There was no difference in the rates of serious adverse events between the vasopressin and norepinephrine groups. Infusions of low-dose vasopressin (0.03 U per minute) increased plasma vasopressin levels to approximately 70 to 100 pmol per liter from extremely low baseline vasopressin levels (median, 3.2 pmol per liter). Consistent with at least 14 previous trials in humans10,11,12,13,14,20,21,22,23,24,25,26,27,28 of low-dose vasopressin (≤0.1 U per minute), vasopressin infusion allowed a rapid decrease in the total norepinephrine dose while maintaining mean arterial pressure.10,11,12,29

Our study was prospectively powered to detect an absolute difference in mortality of 10% from an expected 60%. However, the observed mortality rates in both the vasopressin and norepinephrine groups were considerably lower than those in previous studies, perhaps because of overall improvements in the care of patients who have septic shock. Nonetheless, our data exclude with 95% confidence a harm associated with the use of vasopressin that was greater than 2.9% or a benefit that was greater than 10.7%.

The overall rates of serious adverse events were approximately 10% each in the vasopressin and norepinephrine groups. Previous studies raised the possibility that vasopressin infusion may increase the incidence of cardiac arrest.29 In contrast, we found that of 11 cardiac arrests reported in this study, 8 occurred in the norepinephrine group and 3 occurred in the vasopressin group. Our selection of a low dose of vasopressin (0.03 U per minute) and careful exclusion of patients who had acute coronary syndromes or severe heart failure could account for the lack of adverse cardiovascular effects of vasopressin infusion. If vasopressin becomes routine therapy and is given at higher doses or to patients with septic shock who have coexisting heart disease, the adverse reactions to vasopressin could be increased. Other reported adverse effects of vasopressin and norepinephrine include decreased cardiac output,11,14,29 mesenteric ischemia,21,30 hyponatremia (with vasopressin only), skin necrosis,31 and digital ischemia.32 More patients in the vasopressin group than in the norepinephrine group had digital ischemia; one patient in the vasopressin group required surgical intervention.

Our secondary hypothesis was that the beneficial effects of vasopressin as compared with norepinephrine would be more pronounced in the subgroup of patients with more severe septic shock. No significant interaction between treatment group and shock-severity subgroup (as defined a priori) was shown. Some of the analyses we performed suggested that vasopressin may be more beneficial in patients with less severe septic shock. However, the statistical significance of these observations is uncertain, especially because of the many statistical tests performed, and this finding should be considered only as a hypothesis-generating concept to be tested in future trials.33

Several limitations of our trial should be mentioned. The vasopressin was infused over a set range of doses, and we did not measure vasopressin levels as a guide to the dose or the duration of infusion. In addition, in this trial the mean arterial pressure at baseline was 72 to 73 mm Hg, essentially making this a study of the effects of low-dose vasopressin as a "catecholamine-sparing drug," not an evaluation of vasopressin in patients with catecholamine-unresponsive refractory shock. The mean time from meeting the criteria for study entry to infusion of the study drug (12 hours) was greater than the period that Rivers and colleagues4 identified as being important in early goal-directed therapy (6 hours), which may be one reason that we did not find a benefit of vasopressin as compared with norepinephrine.

In summary, we evaluated the effect of low-dose vasopressin (0.03 U per minute) when used in conjunction with catecholamine vasopressors in patients with septic shock. We did not find a significant reduction in mortality rates with vasopressin.

Supported by a grant (MCT 44152) from the Canadian Institutes of Health Research.

Drs. Russell, Walley, and Gordon report serving as officers and holding stock in Sirius Genomics, which has submitted a patent, owned by the University of British Columbia and licensed to Sirius Genomics, that is related to the genetics of vasopressin. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock. Drs. Russell, Walley, and Gordon report being inventors on this patent. Drs. Russell and Walley report receiving consulting fees from Ferring, which manufactures vasopressin. Dr. Russell reports receiving grant support from Sirius Genomics, Novartis, and Eli Lilly; and Dr. Wally, from Sirius Genomics. No other potential conflict of interest relevant to this article was reported.

* Investigators who participated in the Vasopressin and Septic Shock Trial (VASST) are listed in the Appendix.


Source Information

From the iCAPTURE Centre, Vancouver, BC (J.A.R., K.R.W., A.C.G., M.M.S.); St. Paul's Hospital, Vancouver, BC (J.A.R., K.R.W., J.S., A.C.G., M.M.S., D.A.); Ottawa Hospital, University of Ottawa, Ottawa (P.C.H.); Kelowna General Hospital, Kelowna, BC, and University of British Columbia, Vancouver (C.L.H.); Mount Sinai Hospital, Toronto (S.M.); Toronto General Hospital, Toronto Western Hospital, and University of Toronto, Toronto (J.T.G.); and St. Joseph's Hospital and McMaster University, Hamilton, ON (D.J. Cook) — all in Canada; and Alfred Hospital and Monash University, Melbourne (D.J. Cooper); and Royal Melbourne Hospital and University of Melbourne (J.J.P.) — all in Melbourne, Australia.

Multi-Site Study Finds Chemotherapy Break Can Be Recommended For Some Men With Prostate Cancer

Oregon Health & Science University Cancer Institute researchers, in a first-of-its-kind study, have found that even men with advanced prostate cancer can take a much-needed safe break, or holiday, from chemotherapy.

The double-blind, randomized study, led by principal investigator Tomasz Beer, M.D., recently was published in the journal Cancer. Beer is the Grover C. Bagby Endowed Chair for Cancer Research, director of the OHSU Cancer Institute Prostate Cancer Program, and associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.

Beer and his team wanted to know if men with metastatic, androgen-independent prostate cancer cancer that has spread from the prostate and is not affected by the male hormone, androgen could take a break from docetaxel, an intravenous chemotherapy delivery drug that is the gold standard treatment for androgen-independent prostate cancer. Docetaxel works by killing cancer cells and slowing cell growth. However, the drug also can cause side effects, such as hair loss, nausea, loss of appetite and increased chance for infections. Chemo holidays can be a much-needed vacation from these side effects.

Prior to this study, it wasn't known whether stopping chemotherapy would lead to treatment resistance.

"We wanted to see if we could improve the quality of life for these patients by giving them time away from chemotherapy and possibly extend the time their cancer is controlled. Essentially, what we proved is that in selected subjects, chemotherapy holidays are feasible and provided meaningful breaks from treatment," said Beer.

This is the first multi-institutional trial to examine outcomes from intermittent chemotherapy. A total of 250 men participated. Of those, 18 percent entered the intermittent arm of the study. These men previously had responded well to chemotherapy.

The median duration of the first chemo holiday was 18 weeks. On resumption of chemotherapy, it the majority of subjects responded to treatment. Specifically, 45.5 percent of participants responded with a greater than 50 percent reduction in prostate specific antigen (PSA) from their post-holiday baseline; of those, 45.5 percent had stable PSAs for at least 12 weeks; and 9.1 percent developed disease progression. Prostate-specific antigen is a protein produced by the cells of the prostate gland and is present in small quantities in the serum of healthy men, and it often elevates when prostate cancer is present. Most men have less than 4 nanograms. Anything higher can indicate prostate cancer.

The next step, said Beer, is to study the addition of immunotherapy, treating the cancer by working with the immune system, during the chemotherapy holidays.

"Because we know holidays are a good thing, we want to find ways to make them even longer," Beer said. OHSU and Beer have significant financial interest in Novacea, Inc., a company that has a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.

Recurrence Of Breast Cancer Reduced By Test

A new test that examines large sections of the sentinel lymph node for genes expressed by breast cancer could reduce the risk of recurrence and multiple surgeries, doctors say.

The GeneSearch Breast Lymph Node Assay, manufactured by Veridex, L.L.C., a Johnson & Johnson company, is being used at the Medical College of Georgia to examine half of the tissue in the sentinel lymph node, the first place breast cancer typically spreads. The sample represents more than 10 times the amount of tissue examined in traditional biopsies.

And because the test examines the tissue with molecular tools, it is more sensitive, says Dr. Zixuan (Zoe) Wang, molecular biologist and scientific director of MCG's Georgia Esoteric and Molecular Diagnostic Labs, L.L.C.

"When we look at the tissue with the GeneSearch test, we are looking for excessive amounts of mamoglobin and cytokeratin 19, both genes that are expressed more in breast cancer tissue," Dr. Wang says. "If those genes are present in excessive amounts, we know the cancer has metastasized."

MCG is the first place in Georgia to offer the test, which Time Magazine named one of the top-10 medical breakthroughs of 2007.

Done during a lumpectomy, the GeneSearch test uses molecular diagnostic methods to examine more tissue than traditional sentinel node biopsies, reducing the chance of false negative results, says Dr. Stephen Peiper, chair of the MCG Department of Pathology and Georgia Cancer Coalition Distinguished Cancer Clinician and Scientist.

The sentinel node, located in the armpit, filters fluid from the breast.

"During a traditional sentinel node biopsy, a surgeon would remove a node, then the pathologist would cut that section in half and cut that section to a quarter of the original sample size," Dr. Peiper says. "They then would cut wafer-thin slices from those sections, freeze and stain them, and look for cancer cells under a microscope. This technique, called frozen section, would be done during the lumpectomy surgery. If the tissue is positive for cancer cells, the surgeon removes more nodes from the patient, but if it is negative, the surgery is over."

The problem with that type of test, he says, can come when pathologists review more tissue slices during a confirmatory second test, called a permanent section and done a day later.

Permanent section tests are done the day after surgery because the tissue is set with a fixative that causes proteins in cells to harden for better examination.

"The cancer cells may not have been present in the part of the node that we looked at the day before in the frozen section," Dr. Peiper says. "But on the second day, we may find them in the other section. We perform both the traditional test and the new GeneSearch molecular test in parallel to provide the best care for our patients."

The larger the sample, he says, the better the chance of catching the cancer during the intraoperative test.

"If there are small amounts of cancer cells in the whole node, we may or may not see those with the traditional tests, because we only examine a small section of tissue," he says. "With this technology, we increase the chance of detecting them."

Nearly 20 percent of women with negative nodes confirmed by a traditional biopsy end up having a recurrence and metastasis, Dr. Peiper says.

"There is a higher false-negative rate with traditional sentinel node biopsies," says Dr. Scott Lind, professor and chief of the MCG Section of Surgical Oncology. "If that happens, the patient has to come back in for another surgery to take out more lymph nodes that have likely harbored the breast cancer cells."

In clinical trials, the new test correctly identified more than 95 percent of patients whose cancer had spread to their lymph nodes, according to Veridex, L.L.C.

"This will help us provide better care to patients and better overall treatment," Dr. Lind says.

Who Benefits From Antidepressants? US Health Inequities

A new study published today in PLoS Medicine suggests that antidepressants only benefit some, very severely depressed patients.

"New generation" antidepressants, such as fluoxetine (Prozac) are widely prescribed for the treatment of clinical depression. However some studies have suggested that these drugs do not help the majority of depressed people get better by very much. Irving Kirsch, from the University of Hull, and his colleagues, studied this question in closer detail, looking at whether a patient's response to antidepressant therapy depends on how badly depressed they are to start out with.

Kirsch and colleagues used a technique called "meta-analysis", where they put together data on clinical benefit from all the trials submitted to the US Food and Drug Administration for four drugs: fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat / Paxil). (The researchers also wanted to include sertraline and citalopram, but couldn't find all the relevant data for those two drugs). By including data from unpublished as well as published trials, the researchers set out to avoid bias that might come from non-publication of disappointing findings.

When the data from all of these trials had been put together, the improvement in depression amongst patients receiving the trial drug, as compared to those receiving placebo (dummy tablets), was not clinically significant in mildly depressed patients or even in most patients who suffer from very severe depression. The benefit only seemed to be clinically meaningful for a small group of patients who were the most extremely depressed to start out with. This improvement seemed to come about because these patients did not respond as well as less depressed patients to placebo, rather than responding better to the drug.

Irving Kirsch, summarising the paper, says: "Although patients get better when they take antidepressants, they also get better when they take a placebo, and the difference in improvement is not very great. This means that depressed people can improve without chemical treatments."

Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective

Trial Finds Tenofovir Gel Safe For Daily Use And Most Women Adhered To Study Regimens

A vaginal microbicide that incorporates an antiretroviral (ARV) drug normally used to treat people with HIV is safe for sexually active HIV-negative women to use every day over an extended period, suggest results of a clinical trial of tenofovir topical gel. Moreover, most of the women who participated in the study conducted in India and the United States adhered to a regimen involving either daily or sex-dependent use of the gel, report researchers from the U.S. National Institutes of Health-funded Microbicide Trials Network (MTN) at Microbicides 2008, an international meeting taking place Feb. 24-26 at the Hotel Ashok in New Delhi.

The findings, presented for the first time, are a significant boost to HIV prevention efforts focused on the potential of "next-generation" microbicides to curb infection rates in women. Globally, nearly half of those living with HIV/AIDS are women, and between 70 and 90 percent of all HIV infections in women are due to heterosexual intercourse. In India and many other parts of the world, even married women and women with steady partners are at risk.

In this Phase II study, called HPTN 059, researchers wanted to understand if tenofovir was safe to use every day for six months compared to its use prior to each act of sex, and if women were able to adhere, or follow, each regimen. Researchers found both approaches equally safe and women's adherence to product use similar. Interestingly, most participants also said they would be willing to apply gel, including daily, if one were found effective to prevent against getting HIV from their sexual partners.

Microbicides are products designed to prevent the sexual transmission of HIV when applied topically on the inside of the vagina or rectum. Tenofovir gel is among a newer class of candidate microbicides that differ from early types because they have specific action against HIV. In addition, because tenofovir gel and similar products are longer acting, their use may not be required before each act of sex, which is not always practical or desirable for some women.

"Finding that daily use is both safe and feasible is important because we believe a daily approach may provide more sustainable protection against the virus in women who can't always predict when they will have sex. Based on what we have learned we can proceed with greater confidence on a path that will answer whether tenofovir gel and other gels with HIV-specific compounds will be able to prevent sexual transmission of HIV in women when other approaches have failed to do so. It is a critical time for all of us engaged in HIV prevention, and I truly believe we are turning a corner," said Sharon L. Hillier, Ph.D., professor and vice chair for faculty affairs, and director of reproductive infectious disease research in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, who is MTN principal investigator and led the study.

According to UNAIDS, women represent nearly half, or 46 percent, of the 33.2 million people living with HIV/AIDS worldwide, and they are more than twice as likely as men to acquire HIV through sexual intercourse, due to both biological and cultural factors. Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot successfully negotiate condom use with their male partners.

HPTN 059 involved 200 sexually active HIV-negative women: 52 were enrolled at the University of Alabama at Birmingham (UAB) in Birmingham, Alabama; 48 at Bronx-Lebanon Hospital Center, Bronx, New York; and 100 women entered the study at the National AIDS Research Institute in Pune, India. The mean age was 32 and 64 percent of the women were married. All but one of the women at the Indian site were married compared to 28 percent of the women at the two U.S. sites.

Once enrolled, women were randomly assigned to one of four groups: tenofovir gel applied daily; tenofovir gel applied up to two hours before sex; placebo gel (without an active drug) used every day; or placebo gel applied prior to sex. Because the tenofovir and placebo gels look the same, neither researchers nor participants knew who had been assigned to use which gel during the six-month study period. Women were assessed at one month, three months and six months. Throughout the study, participants received free condoms and HIV risk-reduction counseling as well as routine testing and treatment for sexually transmitted infections.

The study found no differences in liver, blood and kidney function between the groups of women using either regimen of tenofovir gel and the groups assigned to use placebo, nor were there differences in these safety measures between groups using daily gel and groups using gel with sex. Likewise, researchers report no statistical differences in the development of genital symptoms such as itching and burning, which are considered minor. One woman became pregnant and stopped gel use. No participants acquired HIV during the study.

Adherence to treatment was also similar. According to structured interviews, 80 percent of the women instructed to use gel within two hours of having sex said they complied with the regimen. Of the women in the daily-use groups, an average of 83 percent reported study gel use in the past week. The two most cited reasons women gave for not using gel was menstruation (41 percent) and forgetting (23 percent).

Overall, 41 percent of the women indicated there was nothing they disliked about using the gel and 39 percent said it was easy to use. Other attributes of the gel women identified included its potential for protecting against HIV (19 percent), its smell and appearance (14 percent) and that it made sex more pleasurable (12 percent). Thirty-two percent didn't like that the gel was messy, but none of the women said sex was made less pleasurable because of the gel.

Importantly, when asked if they would use the gel if it were found to help prevent people from getting HIV, 90 percent of the women who had been assigned to use the gel at the time of sex and 96 percent of the women who had been asked to use gel daily said yes.

"Women are definitely willing to use a gel to protect against sexual transmission of HIV. That's very encouraging," Dr. Hillier commented.

HPTN 059 also evaluated how the active ingredient in the gel was absorbed from the vagina into the blood and vaginal tissue; and looked at the effects of prolonged use on vaginal flora, the vagina's naturally protective population of microorganisms; and whether the activity of certain immune system molecules called cytokines could serve as a useful measure, or marker, for assessing the safety of microbicides. Results of these evaluations are not yet available.

HPTN 059 was conducted by the Microbicide Trials Network (MTN), a clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). Prior to the establishment of the MTN, HPTN 059 study was led by the NIAID-funded HIV Prevention Trials Network (HPTN), from which the study gets its name.

At the site level, HPTN 059 was led by Smita Joshi, MBBS, in Pune, India; Jessica Justman, M.D., at Bronx-Lebanon Hospital; and Craig Hoesley, M.D., UAB.

In its pill form, tenofovir is a mainstay of one of the most widely used regimens for treating HIV. The active ingredient in tenofovir gel belongs to a class of anti-retroviral drugs called nucleotide reverse transcriptase inhibitors, which act against HIV by targeting a key enzyme the virus needs to copy itself before taking over a host cell. The topical gel form of tenofovir was not developed as treatment for HIV but as an approach to prevent the sexual transmission of HIV. Both oral and topical formulations were developed by Gilead Sciences, Inc., of Foster City, California, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia, in December 2006.

MTN will launch a series of other trials that will further evaluate the safety and adherence of tenofovir gel as well as look at its effectiveness for preventing HIV. Researchers will soon begin enrolling participants into MTN-002, the first trial of a candidate microbicide in pregnant women that seeks to understand the extent of drug absorption during pregnancy and the degree to which the active ingredient in tenofovir gel can be transferred to the fetus. Another trial, MTN-001, will be the first direct comparison of oral and vaginal gel preparations of tenofovir - looking at differences in drug absorption (systemically and locally) and adherence and acceptability of each approach separately and in combination. Finally, the VOICE Study (Vaginal and Oral Interventions to Control the Epidemic) will be the first effectiveness trial of a microbicide that women use every day instead of at the time of sexual intercourse. Moreover, VOICE will be the only trial evaluating two promising HIV prevention approaches in the same study: tenofovir gel and pre-exposure prophylaxis, or PrEP, an HIV prevention approach that involves daily use of oral anti-retrovirals.

Currently, tenofovir gel is being evaluated in a Phase IIb study being conducted at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban. The study, known as CAPRISA 004, will enroll 980 women. Unlike VOICE, researchers are evaluating a dosing strategy timed around sexual intercourse.

Other microbicide products have been or are currently being tested in clinical trials, although none is yet approved or available for use by women.

Congress Likely To Debate Source Of Funds For FDA Oversight Of Direct-to-Consumer Prescription Drug Advertisements

The FDA budget for oversight of direct-to-consumer prescription drug advertisements in fiscal year 2008 is "larger than the past five years combined," but "whether that level of funding will be sustained and continue to come from taxpayers -- or will be raised from drug makers through new user fees -- is likely to be battled out in Congress," USA Today reports.

In FY 2008, FDA received $6.1 million to determine the fairness and accuracy of DTC ads, compared with $2.2 million in FY 2007 and $1 million in FY 2006. FDA officials said that the agency plans to hire additional employees to review more DTC ads. FDA, which currently has 13 employees who review DTC ads, received materials for 12,616 ads last year.

In his FY 2009 budget request, President Bush seeks $14 million in user fees from the pharmaceutical industry to finance 27 additional FDA employees who review DTC ads. In exchange, FDA would review DTC television ads within 45 days and before the ads begin to air.

The Pharmaceutical Research and Manufacturers of America supports the use of user fees to finance FDA oversight of DTC ads. According to PhRMA, expedited FDA reviews of DTC ads would "help drug makers meet marketing goals and lessen the risk of running ads later cited by the FDA for false or misleading content," USA Today reports.

However, some Democratic lawmakers -- such as House Appropriations Subcommittee on Agriculture, Rural Development, FDA and Related Agencies Chair Rosa DeLauro (D-Conn.) -- oppose the use of user fees to finance FDA oversight of DTC ads. "Congress should provide a direct appropriation in order to minimize industry influence in the FDA," DeLauro said (Schmit, USA Today, 2/25).

FDA Authority Over Imports
In related news, HHS Secretary Mike Leavitt said that the Bush administration supports a proposal that would expand FDA authority over medications and foods manufactured abroad for distribution to the U.S., the Wall Street Journal reports. In a letter to Reps. Joe Barton (R-Texas) and John Shimkus (R-Ill.), Leavitt wrote that, because companies abroad often can "deny U.S. officials access to their facilities without any adverse consequences," such a proposal "would better enable FDA to address criminal conduct that occurs entirely outside of the United States and threatens the health and safety of consumers within the United States."

Leavitt sent the letter in response to a request from Barton and Shimkus, who have lobbied for such a proposal since 2000. Barton said, "The secretary's support is good news. We have to get this right, and we have to get it right soon because the volume, variety and the complexity of products arriving from overseas is increasing every day" (Zhang, Wall Street Journal, 2/23).

Opinion Piece
The "unfolding tragedy" in which hundreds of U.S. residents experienced severe allergic reactions or died after they received injections of "Chinese-made heparin has its roots in a spectacular example of bad government that some federal watchdogs started barking at a decade ago," but lawmakers "simply did not respond adequately to the warnings," syndicated columnist Terence Jeffrey writes in the Washington Times.

A 1998 investigation conducted by the Government Accountability Office found that FDA "did not possess a complete and reliable list of the foreign manufacturers producing drugs" and that the system "put Americans at risk," Jeffrey writes. In November 2007, GAO presented to the House Energy and Commerce Subcommittee on Oversight and Investigations the results of a recent investigation that found FDA "still did not have a complete and reliable list of foreign factories making drugs," according to Jeffrey.

He concludes, "Will another decade pass before politicians fix the FDA?" (Jeffrey, Washington Times, 2/24).

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

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).

Antidepressants Only Benefit The Severely Depressed

A new study by researchers in the UK suggests that antidepressants only benefit the very severely depressed and are no more effective than a placebo for everyone else.

The meta-analytical study (ie one that systematically pools the results of other studies) is the work of Dr Irving Kirsch, from the University of Hull, and his colleagues, and is published today, 26th February, in the open access journal PLoS Medicine.

Antidepressants are prescribed for the treatment of clinical depression, and the most widely used are the "new generation" drugs, the SSRIs such as fluoxetine (Prozac) and venlafaxine (Effexor).

Previous meta-analytical studies of antidepressants have already suggested they have only modest benefits over placebos, and the authors pointed out that when data from unpublished trials are included, the benefits are so small they fall below the criteria for clinical significance. What has not been clear in the past however, is whether within this overall result, the effectiveness of antidepressants depends on how severely depressed patients are when they start treatment.

Kirsch and colleagues pooled all the available full data sets from all clinical trials submitted to the US Food and Drug Administration (FDA) for licensing four of the new generation of antidepressants, the SSRIs fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat, Paxil). The data came from both published and unpublished trials.

The point of including data from unpublished as well as published trials, is to avoid potential bias arising from the omission of "disappointing" unpublished findings.

SSRI stands for "selective serotonin reuptake inhibitors". This new type of antidepressant, like the older ones, works by attempting to stabilize chemicals in the brain that influence mood, except that SSRIs specifically target and increase the circulating levels of a brain chemical called serotonin, a neurotransmitter that regulates mood. They do this by inhibiting the reuptake of serotonin so that more of it is available for binding to cell receptors.

Using meta-analytical techniques (a way of pooling data from a range of studies as if they were one big study with broadly the same objectives) the authors assessed the relation between the initial severity of depression and the improvements shown by drug and placebo groups, as well as the relation between initial severity and differences in drug-placebo improvement scores.

The results showed that:

* Drug-placebo differences got bigger as initial severity went up.

* This difference was hardly noticeable at moderate levels of initial depression, went up to a relatively small difference for patients with severe depression, and reached a level that would be classed as clinically significant only in those patients at the extreme end of the very depressed scale.

* The improvement seemed to result from the most severely depressed patients not responding as well to placebo compared to their less depressed counterparts, than because they responded better to the active drug.

Kirsch and colleagues concluded that:

"Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients."

"The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication," they added.

In other words, the difference in effect between drug and placebo was only clinically significant in those patients who were very severely depressed at the start of their treatment and this effect was more likely due to a weaker response to the placebo than a stronger response to the drug itself in that group.

This study is important because although licensing authorities like the FDA in the US and NICE (National Institute for Health and Clinical Excellence) in the UK have approved SSRIs for treating depression, there are nagging doubts about how effective they are.

Depression, which affects about 1 in 6 people at some point in their life, is a serious medical condition characterized by imbalances in brain chemicals that regulate mood. The illness, which can last for months and sometimes years, makes a person feel unmotivated, worthless, hopeless, and sometimes even that life is so futile it would be better to be dead. Depression is often a cause of suicide.

Severity of depression is measured using a questionnaire called the Hamilton Rating Scale of Depression (HRSD) which comprises up to 21 items. If the total score comes to 18 or more, the person is classed as severely depressed.

For an antidepressant to receive a license, clinical trials have to show that it can significantly improve the HRSD score compared to a placebo.

Different countries have slightly different clinical criteria for how much the HRSD score has to improve by before the drug can be licensed to treat depression. In the UK, NICE require that the drug show an improvement in the HRSD score of 3.

A previous meta-analysis of published and unpublished trials sent to the FDA for licensing these drugs showed they only have an average benefit of 1.8 HRSD points.

The reason this study was done was to find out if underneath this 1.8 average there might be subgroups of patients for whom the improvement score was significantly higher, perhaps within the range required by NICE.

And indeed, this is what Kirsch and colleagues found: the clinical criteria were only met when the drugs were used to treat the most severely depressed patients, that is ones with an initial HRSD score of 28 or more, at the extreme end of the scale. And perhaps just as important, is the finding that this effect did not arise as a result of responding to the drug, but because of decreased responsiveness to the placebo.

This last, rather surprising finding, provides a new direction for future research.

"Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration."
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al.
PLoS Medicine Vol. 5, No. 2, e45
Published online: February 26, 2008.
doi:10.1371/journal.pmed.0050045

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

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).

Scheduling Of Zolpidem (Stilnox), Australia

The National Drugs and Poisons Schedule Committee (NDPSC) considered the scheduling of zolpidem (contained in the medicine Stilnox) at its February 2008 meeting, held this week, because of concerns relating to reports of potential abuse of this substance.

The NDPSC also considered a number of submissions describing personal accounts of adverse events, including bizarre sleep behaviours and their consequences.

While the NDPSC acknowledges the concerns that members of the public have raised regarding these adverse events, members of Committee concluded that the current Schedule 4 (Prescription Only) status of zolpidem remains appropriate.

In reaching this conclusion, the NDPSC agreed that zolpidem does not meet the criteria for a Schedule 8 (Controlled Drug) medicine. Schedule 8 medicines must demonstrate a substantial risk of abuse, dependence or misuse for illegal purposes. There was no compelling evidence presented to the NDPSC that the abuse potential of zolpidem requires it to be rescheduled.

The NDPSC noted that zolpidem is only available by prescription under the supervision of a medical practitioner and its use should be carefully monitored by the prescribing doctor. It is only indicated for short-term use and should not be used with alcohol. Zolpidem should be used with caution if taking other central nervous system medications, such as antidepressants, under close medical supervision.

The NDSPSC also noted that the TGA has taken several appropriate regulatory actions and is currently continuing its evaluation of Australian and international data on the safety of zolpidem. The NDPSC will be keeping a watching brief on this matter over the coming months.

In accordance with the NDPSC's practice and statutory requirements, a record of reasons for this and other scheduling decisions made at the February 2008 meeting will be publicly available on the NDPSC website on 4 April 2008.

The National Drugs and Poisons Schedule Committee

The NDPSC is a statutory committee established under the Therapeutic Goods Act 1989. It is responsible for determining the classification and scheduling of substances for inclusion in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), together with other related functions. The NDPSC has a wide range of expert and professional members, with jurisdictional memberships from the Commonwealth, States and Territories and New Zealand.

The NDPSC is required to publish a notice in the Gazette before and after each meeting, which includes an invitation to the public to make submissions.

Scheduling and voting procedures, and the issues the NDPSC must take into account in reaching a decision, are set out in the Act and its associated regulations.

Decisions of the NDPSC are made by a majority of the members present and voting at a NDPSC meeting and must include a majority of the jurisdictional members present and voting. There are eleven jurisdictional members comprising of the Commonwealth (1), states and territories (8) and New Zealand (2). However, only one New Zealand representative is counted as a jurisdictional member for the purposes of voting.

As part of its statutory obligations, the NDPSC publishes records of reasons for its scheduling decisions. This record is published on the NDPSC website approximately six weeks after each meeting. The record of reasons for the February 2008 NDPSC Meeting will be released around 4 April 2008 and can be found here.

http://www.tga.gov.au

Improved Treatment For Crohn's Disease

An international research study, published in The Lancet, has thrown into question the current method of treating Crohn's disease - opening the door to a safer and more effective treatment option for sufferers of the chronic disease.

"Our study clearly demonstrated that this alternative treatment method was more effective at inducing disease remission than the conventional method," said Dr. Brian Feagan, Director of Robarts Clinical Trials at Robarts Research Institute at The University of Western Ontario. Dr. Feagan coordinated the research trial and is an author on the study. "Not only were patients more likely to get their disease under control, but they were also spared exposure to steroids - the extended use of which is linked with metabolic disease and even increased mortality. It's simply a safer, more effective treatment method."

Called a "step-up" approach, the conventional treatment for Crohn's disease involves first administering steroids in order to control the patient's symptoms (abdominal pain and bloody diarrhea); the next step involves administering immune-suppressing drugs, which prepare the body to receive the third medication - an antibody that curbs the inflammatory response at the root of the disease.

The alternative strategy, called "top-down" therapy, employs early use of immune-suppressing drugs combined with an antibody in order to address the disease from the start. Symptom-treating steroids may never even be needed.

The two-year study was conducted at research centres in Belgium, Holland, and Germany and involved 129 subjects with active Crohn's disease. 64 patients received the conventional step-up treatment and 65 the combined immune-suppressing method (top-down). 60% of the top-down subjects were symptom-free by the 26th week of the study, compared to only 36% of the step-up subjects.

"This study is a milestone in the management of Crohn's disease," said lead author Dr. Geert D'Haens, of the Imelda GI Clinical Research Centre at the Imelda Hospital in Bonheiden, Belgium. "It does not look at the effects of single drug intervention but at strategies to alter the natural history of this chronic destructive condition. All 'classic' paradigms for the management of Crohn's disease need to be questioned."

The impact of the study goes beyond Crohn's disease. "We've seen similar results in top-down, step-up studies of rheumatoid arthritis," said Dr. Feagan, "suggesting that the top-down approach could be the best treatment method for other chronic auto-immune diseases such as ulcerative colitis."

Avastin Gets Surprise Breast Cancer Boost From FDA

Genentech's Avastin, a drug which is currently used to treat colon and lung cancer, has been approved by the FDA for breast cancer treatment. Earning approximately $2.3 billion in the USA alone in 2007, this new approval is expected to boost Avastin sales by at least $500 million. Experts had expected the Food and Drug Administration (FDA) to either delay or turn down Genentech's breast cancer application after an Advisory Panel narrowly recommended rejecting breast cancer treatment with Avastin last December.

New positive data was published recently - A Phase III study(E2100) that showed that Avastin in combination with paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease progression or death compared to patients treated with paclitaxel alone and a doubling in progression-free survival (PFS) (based on a hazard ratio of 0.48; p<0.0001).

Roche Holding AG, which is a major holder of Genentech stocks, markets Avastin worldwide outside the USA.

The FDA accelerated approval is for Avastin (bevacizumab), in combination with paclitaxel chemotherapy, for the treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer. Accelerated approval means the FDA approves products for life-threatening diseases based on initial positive clinical data.

Genentech says that it has "shared with the FDA a summary of the results from a second positive Phase III trial (AVADO), and is expecting results from a third Phase III trial (RIBBON I) in first-line metastatic breast cancer in late 2008. A full review of both the AVADO and RIBBON I data by the FDA will be required for the accelerated approval to be converted into a full approval." Data from three randomized trials that are either planned or ongoing will be submitted to the FDA, the company informs.

In a Genentech news release, Kathy Miller, M.D., Associate Professor of Medical Oncology, Indiana University School of Medicine, Head Researcher on the E2100 trial, said "There is no cure for metastatic breast cancer so it is important to control the disease as early and for as long as possible. Now with Avastin plus paclitaxel, we can increase the time a woman's cancer is kept under control, and offer a biologic option to women who previously were limited to chemotherapies alone."

Breast cancer is the second most common cancer for women in the USA; it is the biggest cancer killer of women in the country. Approximately 178,000 women were diagnosed with breast cancer in the United States in 2007. About 40,000 American women died of breast cancer in 2007 (American Cancer Society).

E2100 Trial

E2100 was a multicenter, randomized and controlled clinical trial involving 722 women with previously untreated, locally recurrent or metastatic breast cancer. The women were randomized to receive weekly treatment with paclitaxel every 3 out of 4 weeks, with or without Avastin. Based on an independent, blinded review of patient scans, those treated with Avastin plus paclitaxel experienced median PFS was 11.3 months versus 5.8 months in the paclitaxel alone arm. The independent review showed a similar significance of benefit relative to the initial results presented by the Eastern Cooperative Oncology Group (ECOG) at the American Society of Clinical Oncology annual meeting in 2005. A secondary endpoint of overall survival was 1.7 months longer in the Avastin-containing arm (with a hazard ratio of 0.87), supporting the primary endpoint of PFS. This improvement did not reach statistical significance (p=0.14).

Grade 3/4 adverse events that occurred more often in the Avastin arm included neuropathy (due to longer time on paclitaxel treatment), high blood pressure (hypertension), arterial thromboembolic events and proteinuria. These safety findings were in general consistent with earlier Avastin plus chemotherapy trials and no new safety signals related to Avastin were observed.

Anti HIV Cream , Safe But Did Not Prove It Is Effective

A trial to evaluate an anti-HIV microbicide cream for women has found the product is safe, but it was not able to prove it could prevent male to female transmission of the virus during sex. However, researchers said it was a milestone in the fight to prevent the spread of HIV.

The cream is called Carraguard and is made from carrageenan seaweed. The US Food and Drug Administration (FDA) have given it a "Generally Recognized As Safe" go ahead for oral and topical use.

Carraguard is the first product designed to be a microbicide that has completed the final phase of clinical testing. The trial found it to be safe for vaginal use, but it did not show it was effective at stopping the virus passing from a man to a woman during vaginal intercourse.

The randomized, double blind, phase 3 trial involved 6,202 women and was carried out at three South African sites where the HIV epidemic is acute. It started in March 2004 and finished in March 2007.

The women were equally split into a Carraguard group and a placebo group. Both groups received a topical gel and condoms, and neither participants nor their doctors knew who got the Carraguard and who got the placebo (double blind). All participants also received education about HIV, counselling about safe sex and how to reduce risk of sexually transmitted infections, as well as being medically examined, and tested and treated for curable sexually transmitted infections.

The results showed 134 new infections in the group that used Carraguard and 151 in the placebo group. This translates to an incidence rate of 3.3 infections per 100 woman-years compared to 3.7, respectively, a difference that was not found to be statistically significant.

The researchers found no safety related differences between the placebo and the active ingredient group, and adverse events due to gel application were minor and infrequent.

The researchers said this result was important because of what it means to the development of the next generation of microbicides, of which Carraguard is an important ingredient.

President of the Population Council, Peter Donaldson, said:

"We are disappointed that this trial did not show Carraguard to be effective."

But, he added that the completion of the trial marked a "milestone in HIV prevention research". It has made a big contribution to knowledge about product development, trial design, and the willingness of women and their partners to use a vaginal gel consistently, said Donaldson. The data will be very useful to other researchers working on microbicides.

Director of the Population Council's HIV and AIDS program, Naomi Rutenberg, said:

"The Population Council will use these trial results to accelerate the development of effective means for women to protect themselves against HIV."

In the laboratory, Carraguard was found to be effective at stopping cells from invasion by HIV, and it also stopped mice getting some sexually transmitted infections. Carraguard and similar products based on carrageenan seaweed have been tested widely in trials in the US, Australia, Chile, the Dominican Republic, Finland, South Africa and Thailand, in over 850 men and women.

The US Agency for International Development (USAID) and the Bill & Melinda Gates Foundation funded the trial. Speaking for USAID, their senior science advisor, Jeff Spieler said they always knew it would take a long time to produce a successful microbicide:

"The Population Council has done groundbreaking work in completing this trial, even though we are terribly disappointed that the product was not shown to be effective," said Spieler.

"Now we all have to redouble our efforts to develop a microbicide that women can use to protect themselves," he urged.

Developing effective vaginal microbicides is important because it gives women more options for controlling the spread of HIV and other sexually transmitted infections, especially since current strategies are not always possible.

NIH Hydroxyurea Treatment For Sickle Cell Disease Conference, Feb. 25-27

For many patients, the pain and complications associated with sickle cell disease can have a profound impact on their quality of life, ability to work, and long-term health and well-being. Unfortunately, these challenges are often coupled with significant barriers to care. Hydroxyurea is an FDA-approved therapy for adults with certain forms of sickle cell disease, and acts to increase the percentage of non-sickled red blood cells in circulation. However, concerns remain for both physicians and patients. The conference panel will examine these issues in detail at the upcoming conference, resulting in a summary of what we know and what we need to learn about hydroxyurea treatment for sickle cell disease.

What

Experts will describe the available evidence on hydroxyurea treatment for sickle cell disease, including efficacy, effectiveness, harms, barriers to treatment, and future research needs. Following a series of scientific presentations and open public discussions, an impartial, independent panel will issue a statement of its findings on the final day of the conference, and will hold a press conference at 2:00 p.m. on Wednesday, February 27. Convened by the Office of Medical Applications of Research (OMAR) and the National Heart, Lung, and Blood Institute (NHLBI) of the NIH, this conference is free and open to the public and the media.

The conference presentations, open discussions, and the panel's statement will focus on these questions:

1. What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?

2. What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?

3. What are the short- and long-term harms of hydroxyurea treatment?

4. What are the barriers to hydroxyurea treatment for patients who have sickle cell disease and what are the potential solutions?

5. What are the future research needs?

When

Monday, February 25, 2008 - 8:30 am - 5:30 pm
Tuesday, February 26, 2008 - 8:30 am - 12:00 pm
Wednesday, February 27, 2008 - 9:00 am - 11:00 am
Press Conference: Wednesday, February 27, 2:00 p.m.

Where

Natcher Conference Center
NIH Main Campus - Building 45
9000 Rockville Pike
Bethesda, Maryland 20892

Antidepressants Can Help With Obsessive Compulsive Disorder

Common antidepressant drugs such as Prozac and Zoloft can be effective treatment options for obsessive compulsive disorder (OCD), according to a new review of studies.

Patients who take selective serotonin reuptake inhibitors, or SSRIs, are twice as likely to get some relief from their OCD symptoms as those who take placebo pills are.

However, the drugs have a "modest" effect at best, said Dr. Ghulam Mustafa Soomro, lead review author and honorary research fellow at St. George's Hospital Medical School in London.

"Although SSRIs should be considered potentially effective treatments for OCD patients, treatment decisions need to take account of the potential adverse effects of these drugs," including nausea, insomnia and sexual dysfunction, he warned.

The review of studies appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews like this one draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Many people with OCD seek out therapy that teaches them to confront, tolerate and gradually wean themselves from obsessive and compulsive behaviors.

"This is the primary kind of therapy used for OCD. It teaches patients to pay attention to their internal experiences and tolerate scary thoughts without having to act on them," said Sanjaya Saxena, M.D., director of the Obsessive-Compulsive Disorders Program at the University of California, San Diego School of Medicine. "They learn that nothing terrible happens if they refrain from their usual compulsive behaviors."

Nevertheless the success rates for this type of therapy vary, and "unfortunately, about 25 percent of patients offered this form of treatment refuse it," Soomro said, adding that SSRIs "may offer help to some of these patients."

After reviewing 17 studies that included 3,097 patients, the reviewers concluded that SSRIs were more effective than a placebo in reducing OCD symptoms six to 13 weeks after starting treatment.

None of the drugs stood out above the rest; they all appeared equally effective. However, in most cases, side effects such as nausea and headache were noticeably worse with the SSRIs than with the placebo pills.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.

Soomro GM, et al. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD) (Review). The Cochrane Database of Systematic Reviews 2008, Issue 1.

Health Behavior News Service
Center for the Advancement of Health 2000 Florida Ave. NW, Ste 210
Washington, DC 20009
United States
http://www.hbns.org

Sorafenib (Nexavar) Dropped From Lung Cancer Trial

Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals have stopped a late stage trial of their cancer drug Nexavar (sorafenib) in patients with nonsmall-cell lung cancer (NSCLC), because it was not showing the hoped for increase in survival.

Following a planned interim analysis, the trial's independent data monitoring committee (DMC) concluded that the drug was not going to meet the trial's main goal of improving overall survival.

In the phase 3 trial, a group of patients with squamous cell carcinoma of the lung who took the drug in combination with chemotherapy drugs carboplatin and paclitaxel showed a higher rate of death than a group that received chemotherapy alone.

The trial, which is called ESCAPE (Evaluation of Sorafenib, Carboplatin And Paclitaxel Efficacy in NSCLC), was otherwise showing safety events generally in line with those previously reported, said Bayer in a press statement.

The two drug companies are giving the DMC information to health authorities and other investigators studying the effects of Nexavar and will also be presenting the findings of the trial at a forthcoming scientific meeting.

The companies will also be reviewing the findings of this trial, including the DMC review, to see if they impact any other ongoing lung cancer trials using Nexavar.

Vice president of Therapeutic Area Oncology at Bayer HealthCare Pharmaceuticals, Dr Susan Kelley said that they were disappointed with this result, but the two companies were still very much committed to widening the scope of Nexavar in treating as many cancers as possible and will continue to extend trials to other cancers.

"Nexavar has proven significant clinical benefit for patients with liver cancer and advanced kidney cancer and we will continue to investigate its potential across a wide variety of tumors," said Kelley.

The ESCAPE study was a multicentre, randomized, double-blind, placebo controlled phase 3 trial involving more than 900 NSCLC patients at over 140 clinics in North and South America, Europe and Asia.

The main outcome sought was overall survival, but secondary endpoints included progression-free survival, tumour response, quality of life, and drug safety.

The participants had not received any systematic anti-cancer treatment for lung cancer before the trial, which was open to patients with all types of NSCLC, including squamous cell carcinoma or adenocarcinomas.

The patients were randomized to a drug group and a control (placebo) group. The drug group was given 400 mg of Nexavar, orally, twice a day, while the control group had a placebo. Both groups also had two chemotherapy drugs, carboplatin and paclitaxel. Both groups continued with the drug or placebo alone, after chemotherapy had finished (maintenance phase), until symptoms of tumour progression or side effects showed.

Nexavar (sorafenib) attacks both the tumour cell and the blood vessels that feed it. In studies before clinical trials, the drug showed ability to target kinase proteins thought to be involved in cell growth and development of blood supply, two essential cancer enablers. The kinases involved include: Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is approved for the treatment of liver cancer in over 30 countries and for the treatment of advanced kidney cancer in over 60 countries. It is being evaluated for use with many other cancers such as breast cancer, metastatic melanoma, and as an adjuvant therapy for kidney cancer and liver cancer.

Heparin Chinese Supplier Was Never Checked By Chinese Drug Regulators

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

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.

Unapproved Uses Of FDA-approved Drugs And Medical Devices

The Food and Drug Administration (FDA) issued a preliminary draft guidance regarding the publication of information related to unapproved uses of FDA-approved drugs and medical devices.

Randall Lutter, FDA deputy commissioner for policy, said "Articles that discuss unapproved uses of FDA-approved drugs and devices can contribute to the practice of medicine and may even constitute a medically recognized standard of care. This guidance also safeguards against off-label promotion."

Section 401 of the FDA Modernization Act had previously set out guidelines that permitted the dissemination of information on unapproved uses of FDA-approved drugs and medical devices. If the manufacturers complied with the guidelines when publishing information they were not seen as an attempt to promote the product for non-FDA approved use (off-label use). As Section 401 expired in September, 2006, new guidelines are needed. Hence the issue of the FDA's "Good Reprint Practice" draft guidance.

The draft guidance recommends principles drug/medical device manufacturers should follow when distributing scientific or medical journal reprints, or reference publications.

They should make sure that the article or reference was/is published by an organization which has an editorial board. All conflicts of interests faced by the organization, as well as biases for all authors, contributors or editors linked with the journal article should be disclosed fully. The article should be peer-reviewed and published in accordance with precise procedures.

Additionally, the draft recommends against distribution of special supplements or articles that have been financed by one or more of the manufacturers of the product in the article, and articles that are not supported by convincing medical evidence are considered false and misleading and should not be distributed.

The FDA will have the legal authority to decide whether an article/publication distribution be classed as promotion for an unapproved new use, or whether such activities cause a drug/medical device to be misbranded or adulterated under the Federal Food, Drug and Cosmetic Act.

The FDA is inviting typed comments, which should be submitted within 60 days of the Federal Register notice announcing the availability of the draft guidance.

FDA Approval For SIMCOR(R) (Niaspan(R) / Simvastatin), A Novel Combination Medicine For Comprehensive Cholesterol Management

Abbott received U.S. Food and Drug Administration (FDA) approval for SIMCOR(R), the first fixed-dose combination of two widely prescribed cholesterol therapies, Niaspan(R) (Abbott's proprietary niacin extended-release) and simvastatin. SIMCOR is approved for use along with diet to lower levels of elevated total cholesterol, LDL "bad" cholesterol and triglycerides, and to raise HDL "good" cholesterol in patients with complex lipid disease when treatment with simvastatin or Niaspan monotherapies are not considered adequate.

"Managing cholesterol encompasses many factors, not just lowering LDL. There is a clear need for medicines that both raise good and comprehensively lower the bad components of cholesterol," said Christie Ballantyne, M.D., the Methodist DeBakey Heart and Vascular Center, Houston, and lead SIMCOR investigator. "SIMCOR represents an important new option to help patients reach healthy lipid levels."

An estimated 80 million Americans have high levels of the bad LDL cholesterol, and more than 44 million have low levels of the good HDL cholesterol, which the body uses to remove bad cholesterol from the bloodstream. Studies have shown that along with diet, SIMCOR can help patients with lipid disorders reach their treatment goals by addressing more than just bad cholesterol, targeting multiple lipids with one pill.

The FDA's approval was based on SIMCOR safety and efficacy trial data from more than 640 patients with mixed dyslipidemia and type II hyperlipidemia. In the SEACOAST clinical trial, patients receiving SIMCOR 1000/20mg achieved significant cholesterol improvements over and above what simvastatin 20mg alone provided. Patients treated with SIMCOR 1000/20mg had additional lipid improvements beyond simvastatin 20-mg treated baseline, with additional LDL reductions of 12 percent and an additional 21 percent HDL increase compared to a 7 percent decrease in LDL and an 8 percent increase in HDL with simvastatin 20mg alone. Furthermore, SIMCOR reduced triglycerides by an additional 27 percent compared to 15 percent with simvastatin 20mg alone.

SIMCOR was generally well tolerated by patients in clinical studies. Six percent of patients discontinued therapy due to flushing, the most commonly reported side effect of SIMCOR and niacin-based therapies. Flushing can be minimized by taking aspirin or an NSAID 30 minutes prior to taking the medication at bedtime. Flushing may subside over several weeks of consistent SIMCOR use.

"With SIMCOR, doctors now have a new option for helping patients reach their LDL and HDL cholesterol treatment goals with a combination of two proven therapies," said Eugene Sun, M.D., vice president of Global Clinical Development for Abbott. "Abbott is committed to bringing forward new cholesterol therapies, and SIMCOR represents a new treatment option for patients in Abbott's rapidly expanding portfolio of cholesterol treatments for lipid disorders."

The American Heart Association, National Cholesterol Education Program (NCEP) and American College of Cardiology recommend more aggressive treatment of HDL to reduce cardiovascular risk. Cholesterol and other lipids can build up in the bloodstream forming plaque and restricting blood flow, which can lead to heart disease. According to NCEP guidelines, a reduction in LDL of 1 percent is associated with a 1 percent reduction in heart disease risk. Additionally, raising HDL by 1 point is associated with a 2 percent heart disease risk reduction.

Abbott is committed to the continued research of its products and has sponsored the National Heart Lung and Blood Institute's AIM-HIGH outcomes study. The study is designed to evaluate the effects of niacin extended- release and simvastatin in reducing cardiovascular events in patients with existing heart disease. AIM-HIGH began enrolling patients in 2005 with final results expected to be reported in 2011.

SIMCOR Indications

SIMCOR is the combination of two cholesterol-lowering medications: niacin extended-release (Niaspan(R)) and simvastatin. SIMCOR is used along with diet to lower levels of total cholesterol, LDL "bad" cholesterol and triglycerides, and to increase HDL "good" cholesterol. SIMCOR is used when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate, and when diet and other non-drug measures alone have not been successful. Patients should stay on a diet low in saturated fat and cholesterol while taking this medicine. No additional benefit of SIMCOR on heart disease over and above that shown for niacin alone and simvastatin alone has been demonstrated.

Important Safety Information About SIMCOR

SIMCOR should not be used by people with liver problems, stomach ulcers, or serious bleeding problems; in women who are pregnant, may become pregnant, or nursing; and in people allergic to any product ingredient. Patients should contact their health care provider if symptoms of unexplained muscle pain, tenderness, or weakness occur, as this may be a sign of a serious but rare muscle disorder, from which rare cases of death have occurred. Health care provider should be informed about any other medications, vitamins, or nutritional supplements people are taking to avoid possible serious drug interactions. SIMCOR should not be substituted for equivalent doses of immediate-release niacin. Liver damage has been reported when substituting sustained-release niacin products with immediate-release niacin at equivalent doses. Always check with a health care provider before changing medication. SIMCOR should be used with caution by patients who consume large amounts of alcohol. Health care providers may do simple blood tests before and during treatment with SIMCOR to check for liver problems.

SIMCOR may cause an increase in blood sugar levels. Patients with diabetes should report any changes in blood sugar levels to their health care provider. Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Flushing (warmth, redness, itching, and/or tingling of the skin) is the most common side effect and may become less frequent over time. Additional symptoms may include rapid or pronounced heartbeat, shortness of breath, sweating, chills, dizziness, fainting, and/or swelling. Flushing may vary in severity and is more likely to occur when starting therapy or during dose increases. By taking SIMCOR at bedtime, flushing will most likely occur during sleep. If awakened by flushing, patients should take their time getting up, especially if feeling dizzy, faint, or taking blood pressure medications. Other common side effects may include headache, itching, nausea, back pain, and diarrhea.

About Niaspan

Available since 1997, Niaspan is the only FDA-approved, once-daily extended-release prescription formulation of niacin for treating abnormal cholesterol levels.

Niaspan Indications

Niaspan is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate, to reduce elevated total cholesterol, LDL- C, Apo B, and triglyceride levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent non-fatal myocardial infarction. In patients with coronary artery disease and hypercholesterolemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.

Important Safety Information About Niaspan

Niaspan is contraindicated in patients with allergies to any of its ingredients, active peptic ulcer disease, significant or unexplained persistent liver dysfunction, or arterial bleeding. Niaspan should not be substituted for equivalent doses of immediate-release niacin. Niaspan should be prescribed with caution in patients who consume substantial amounts of alcohol and/or have a past history of liver disease. Liver function tests should be performed on all patients during therapy with Niaspan. Use of Niaspan with other lipid-altering medications called statins may increase the risk of rhabdomyolysis, a rare condition that causes muscles to breakdown. The most common side effect with Niaspan is flushing of the skin. Patients with diabetes should carefully monitor their blood sugar and report changes to their doctor. Other commonly reported side effects include indigestion, headache, pain, abdominal pain, nausea, itching, diarrhea, runny nose, vomiting and rash.

Important Safety Information About Simvastatin

Simvastatin is a prescription tablet and isn't right for everyone, including women who are nursing or pregnant or who may become pregnant, and anyone with liver problems. Unexplained muscle pain or weakness could be a sign of rhabdomyolysis, a rare but serious side effect and should be reported to a doctor right away. Simvastatin may interact with certain foods or other medicines including lipid-lowering medications called fibrates or niacin, increasing the risk of getting this serious side effect. Patients should tell their doctor about any other medications they are taking. The most common side effects are headache, abdominal pain, and constipation.

Positive First-line Phase 1 Safety And Efficacy Data With Picoplatin In Metastatic Prostate Cancer Patients

Poniard Pharmaceuticals, Inc. (Nasdaq: PARD), a biopharmaceutical company focused on oncology, announced that it is presenting safety and efficacy data in prostate cancer patients from its Phase 1 study of picoplatin, the Company's lead product candidate, at the 2008 Genitourinary (GU) Cancers Symposium, a meeting of the American Society of Clinical Oncology (ASCO) that is being held in San Francisco.

The poster presentation includes safety and efficacy data from a dose-escalating Phase 1 study of picoplatin in combination with full-dose docetaxel (75 mg/m squared) with prednisone as a first-line treatment for metastatic hormone refractory prostate cancer (mHRPC). The Phase 1 study sought to establish the maximum tolerated dose of picoplatin and provide information on the safety and efficacy of picoplatin in combination with docetaxel and prednisone, the standard of care for the first-line treatment of mHRPC.

"The data we have generated with picoplatin in prostate cancer indicate a PSA (prostate specific antigen) response of 65 percent which suggests an improvement compared to docetaxel therapy alone," said Jerry McMahon, Ph.D., chairman and CEO of Poniard Pharmaceuticals. "In addition, the tolerability of picoplatin with full-dose docetaxel supports our ongoing Phase 2 study that we believe will confirm and extend these initial findings. The combination of platinums and taxanes, such as docetaxel, is used to treat many other solid tumors, such as non-small cell and ovarian cancers. We believe that our data support additional evaluation of picoplatin and docetaxel combinations in these cancers in addition to prostate cancer."

In the combination Phase 1 dose-escalating study, 33 patients were treated with one of four doses (60, 80, 100 or 120 mg/m squared) of picoplatin, as well as either 60 mg/m squared or 75 mg/m squared (full-dose) docetaxel plus 5 mg prednisone twice daily. Nine patients received 120 mg/m squared picoplatin and 75 mg/m squared docetaxel every 21 days plus 5 mg prednisone twice daily. This dose, which is also the dose currently under study in the Phase 2 trial, was well tolerated.

Hematological toxicity, including neutropenia, anemia and thrombocytopenia, was dose-dependent and reversible. Neutropenia was the dose-limiting toxicity (DLT). Mild neuropathy (grade 1) was observed in 3 of 33 patients (9 percent) and was unrelated to cumulative picoplatin dose. Neuropathy was infrequent, and no neuropathy of grade 2 or greater was observed. PSA response rate was 65 percent (20 of 31 evaluable patients). Survival data are not yet available. Patient withdrawal from study treatment occurred from death in four patients, progressive disease in eight patients, and withdrawal of consent in one patient. Patients in the Phase 1 trial received a median number of 7 cycles, and 13 of 33 patients completed the maximum of 10 cycles of treatment according to the study protocol.

Based on safety and efficacy data from the Phase 1 study, the recommended Phase 2 regimen of intravenous picoplatin (120 mg/m squared) and docetaxel (75 mg/m squared) every 21 days with prednisone (5 mg) orally twice daily is being evaluated in a Phase 2 study in chemotherapy naive mHRPC patients. PSA response is the primary endpoint; secondary endpoints include radiological response using RECIST criteria, time to progression and survival (1-year, progression-free and overall). The Phase 2 trial completed enrollment in December 2007. The Company expects to present the results of this study in scientific forums later this 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 800 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 mHRPC, 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 from the U.S. Food and Drug Administration 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 colorectal cancer. 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.

Cell Genesys Reports Association Between Immune Response And Patient Survival In Phase 2 Trial Of GVAX Immunotherapy For Prostate Cancer

Cell Genesys, Inc. (Nasdaq: CEGE) reports the results of an analysis examining the potential association between immune responses to GVAX immunotherapy for prostate cancer and increased patient survival in a Phase 2 trial in patients with metastatic, hormone refractory prostate cancer (HRPC). More than 400 patient-specific GVAX-induced antibody responses were identified in the sera of the treated patients by three different biochemical techniques confirming, as previously reported, that GVAX treatment results in a broad, multi-antigen immune response. An ongoing analysis of these GVAX-induced antibody responses has shown that at least two of the antibody responses are associated with patient survival, an association that is independent of the dose and number of treatments administered. These data will be presented today by Dr. Thomas Harding and colleagues from Cell Genesys at the American Society of Clinical Oncology's Genitourinary Cancer Symposium being held in San Francisco, California.

Cell Genesys has previously reported the results of two multicenter Phase 2 trials of GVAX immunotherapy for prostate cancer in metastatic HRPC. The second of these two trials enrolled 80 patients. The serum of 65 patients (the total number for whom adequate sera were available) were examined to determine each patient's immune response to two specific antigens, HLA-A24 and FLJ14668, following GVAX treatment. Thirty-four of 65 patients demonstrated an FLJ14668-specific antibody immune response. These 34 patients had a median survival of 43 months, compared to a median survival of 21 months achieved by the patients who did not generate anti-FLJ14668 antibodies (p=0.002). Twenty-two of these 65 patients received a dose of GVAX immunotherapy for prostate cancer comparable to that being evaluated in ongoing Phase 3 clinical trials. Of these 22 patients, 16 patients (73 percent) mounted an immune response to FLJ14668. These 16 patients achieved a median survival of 44.9 months. As previously reported, the median survival for all 22 patients in this treatment group was 35.0 months. Finally, of the 58 patients who were HLA-A24 genotype negative and therefore potentially able to mount anti-HLA-A24 specific antibody responses, 30 patients were found to be anti-HLA-A24 antibody positive. These 30 patients had a median survival of 43 months, compared to a median survival of 18 months in the patients who did not generate anti-HLA-A24 antibodies (p=0.05). Importantly, the apparent associations between the presence of these two specific antibody responses and survival were shown by multivariate analysis to be independent of both dose and duration of treatment.

"The findings being reported today indicate a potential association between two specific GVAX-induced antibody responses and patient survival, an association consistent with the proposed mechanism of action for this product. We look forward to expanding these findings in a prospective analysis of the sera of patients treated in our two randomized controlled Phase 3 trials," stated Peter K. Working, Ph.D., senior vice president of research and development at Cell Genesys. "Since GVAX immunotherapy for prostate cancer is a multi-antigen product that can induce a broad immune response, we believe we have a unique opportunity to identify the widest possible array of specific antibody responses that may be associated with clinical benefit."

Cell Genesys is currently evaluating GVAX immunotherapy for prostate cancer in two Phase 3 multicenter, randomized, controlled clinical trials. VITAL-1, which is fully enrolled with 626 patients, is designed to compare GVAX cancer immunotherapy to Taxotere(R) (docetaxel) chemotherapy plus prednisone in HRPC patients with metastatic disease who are asymptomatic with respect to cancer-related pain. The primary endpoint of the trial is an improvement in survival. An interim analysis of the trial was recently conducted by an independent data monitoring committee in the timeframe originally estimated and resulted in the recommendation to continue the trial. The company expects to have enough events to trigger the final analysis of VITAL-1 in the second half of 2009. VITAL-2, which the company expects to fully enroll with approximately 600 patients in the first half of 2009, is designed to evaluate the safety and efficacy of GVAX immunotherapy for prostate cancer used in combination with Taxotere chemotherapy compared to the use of Taxotere chemotherapy and prednisone in HRPC patients with metastatic disease who are symptomatic with cancer-related pain. The primary endpoint of the trial is also an improvement in survival. The company expects to have enough events to trigger an interim analysis of VITAL-2 in the first half of 2009.

About GVAX Cancer Immunotherapies

GVAX cancer immunotherapies are non patient-specific investigational products comprised of whole tumor cells that have been modified to secrete GM- CSF (granulocyte-macrophagecolony-stimulating factor), an immune stimulatory cytokine, and then irradiated for safety. GVAX is administered via intradermal injections on an outpatient basis. To date, over 600 patients have been treated with GVAX cancer immunotherapies in Phase 1 and Phase 2 clinical trials for multiple indications, including prostate cancer, pancreatic cancer, and leukemia. The company is currently manufacturing GVAX immunotherapy for prostate cancer in its bioreactor-based manufacturing plant in Hayward, California, a facility that is also capable of manufacturing the product for commercialization.

About Cell Genesys