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The leaders of four U.S. pediatric oncology groups have announced a plan to form a single pediatric clinical trials organization. The group leaders made the decision at a meeting in July and now face the challenge of designing a new governance system while keeping the existing four systems functional.
"We have just announced our engagement; it's months away from a nuptial agreement," said Sharon Murphy, Chairman of the Pediatric Oncology Group (POG). "We can't just put it all together, nor do we have a clear idea of how it's going to come together. This was a spontaneous decision without a lot of clear step-by-step implementation."
Currently, institutions that conduct pediatric clinical trials belong to one of two groups, POG or the Children's Cancer Group (CCG). Investigators at these institutions collaborate in studies conducted by two additional groups, the Intergroup Rhabdomyosarcoma Study Group, and the National Wilms' Tumor Group. The four groups will begin to form a single administrative structure. "We are going to need time to develop this single organization; we are going to maintain what we are doing now, our 8,000 to 9,000 protocol entries per year," Murphy said.
The merger could allow the groups to leverage their resources at a time when traditional sources for clinical research have been drying up. In recent years, managed care organizations have been cutting into the funds institutions used to finance research. NCI support, too, has been insufficient to meet the needs of a system that has been able to place the majority of patients on clinical trials and produce cure rates that are significantly higher than those in adults. Pediatric and adult cooperative groups are funded at about 60% of the level recommended by peer review.
In addition to leveraging dwindling resources, elimination of duplication in the pediatric trials system could allow the groups to make better use of a financial windfall that is expected to follow the new U.S. FDA policy of extending exclusivity for drugs that are used for pediatric indications. Under the FDA Modernization Act signed into law last November, any drug that has been tested in pediatric populations would qualify for an additional six months of market exclusivity. Thus, a drug that has a five-year chemical entity exclusivity would be protected for five and-a-half years from generic competition for drugs that had been studied in pediatric populations. Additional six-month extensions are possible for drugs that undergo multiple pediatric studies. Exclusivity would be extended for all indications. Pediatric studies would be conducted in response to a "Written Request" issued by the agency.
The regulation has increased the pharmaceutical industry's interest in pediatric research, said Archie Bleyer, Chairman of the CCG. "We have seen a clear-cut effect of the regulation," Bleyer said. "Pharmaceutical companies have been coming to us, instead of the reverse. I have never seen this before in the 27 years I have been treating children with cancer."
Formation of a single cooperative group would make it easier and more cost-effective for the industry to conduct trials, Bleyer said. "Suddenly, we are able to double the number of institutions conducting our trials, which means that we should be able to cut in half the time it takes to conduct a trial."
The proposed merger is a demographic necessity, group leaders say. "In the early ‘70s, the cure rates were low enough that it was much easier to work in smaller groups," William Crist, Chairman of the Intergroup Rhabdomyosarcoma Study Group, said at the Implementation Committee meeting.
In recent years, cure rates in children's cancers have increased dramatically. "When you start with an 80% cure rate and want to show it's 90, you need to do intergroup studies across the board in addition to the other economies of doing business in a streamlined, uniform fashion," Crist said. "What's the point of having multiple groups, if we require all the patients in the U.S., or North America, or the developed world to do the studies?"
Currently, the pediatric groups put between 8,000 and 10,000 patients on clinical trials. This means that 50% to 60% of pediatric cancer patients under age 15 receive care under clinical trials. To keep them on trials, the groups frequently have to convince insurance companies to reimburse patient care costs.
Bleyer said the new group may be able to raise clinical trials participation to 85% among children under 15. "Together, we will be able to study less common cancers we were unable to study alone," Bleyer said. These would include germ cell tumors, retinoblastoma and histiocytosis. Together, these three tumors account for about 10% of cancers in children. "There are also some stages of common diseases that we are unable to study alone," Bleyer said.
Greater efficiency could allow the groups to close what is known as "the adolescent gap," by enrolling a greater number of 15- to 19-year-old patients. Currently, only 5% to 10% of patients in this age group are enrolled in trials. 
Cancer Prevention: Tamoxifen Cut Breast Cancer by 49% in Trial, NSABP Says
Tamoxifen reduced the risk of invasive breast cancer by 49% in women at high risk of the disease who took the drug for five years, compared to women who took a placebo, according to a report of the National Surgical Adjuvant Breast and Bowel Project (NSABP) study P-1. The study also found that tamoxifen reduced the risk of noninvasive breast cancer by 50%. The effect was seen in all age groups and all of the risk categories in the study.
The findings of the study, also known as the Breast Cancer Prevention Trial, were published in the September 16, 1998 issue of the Journal of the National Cancer Institute. The results are updated by six months from the initial release of data from the trial last April. "The updated findings continue to show that the benefits of tamoxifen in reducing the probability of developing a breast cancer remain and are actually stronger than initially reported," D. Lawrence Wickerham, Associate Chairman of the NSABP and Protocol Officer for the study, said in a September 14, 1998 teleconference.
NSABP initially reported a 45% reduction in risk of invasive breast cancer.
Over 13,000 women entered the trial, which began in 1992. Mean follow-up has reached nearly four years, and nearly a third of the women have been followed for more than five years. "The updated findings also continue to show that tamoxifen is associated with an increased risk of endometrial cancer that is about two- to threefold greater than the women receiving placebo, and the same holds true for blood clots in major veins in the body, again a two- to threefold increase," said Wickerham, one of the authors of the report. "This magnitude of increase in blood clots is, however, quite similar to other hormonal therapies, including hormonal replacement therapy after menopause."
The publication of the P-1 findings comes two weeks after the FDA Oncologic Drugs Advisory Committee recommended approval of tamoxifen (Nolvadex, sponsored by Zeneca Pharmaceuticals) for the short-term reduction of risk of breast cancer in high-risk populations. According to the P-1 report, the findings of the study indicate that the following populations should be candidates for the drug:
The study said the following populations "might also be candidates" for tamoxifen:
The NCI has developed a breast cancer risk assessment tool to help health care providers inform women about their risk of developing breast cancer. The software program goes through a list of questions that women can answer to determine their risk of developing breast cancer. The program, which has been nicknamed the "risk disk," will be sent to anyone who signs up for a copy on the NCI Cancer Trials website at http://cancertrials.nci.nih.gov (click on the Sign-up Area, then go to the E-mail Alert Service). A second version of the program is planned to examine the risks and benefits of taking tamoxifen for individual women.
IVAX, Immunex First to File ANDA with FDA for Paclitaxel
The FDA has confirmed that an Abbreviated New Drug Application (ANDA) that is part of a new alliance between IVAX Corporation of Miami and Immunex Corporation of Seattle, for paclitaxel injection is the first filed with the agency. This means that if Immunex and IVAX prevail in patent litigation with Bristol-Myers Squibb, the sponsor of branded drug Taxol, the sponsors of the generic would be entitled to 180 days of shared market exclusivity. The ANDA was originally filed by Immunex. The FDA confirmation follows completion of agreements between Immunex and IVAX to collaborate on bringing a generic paclitaxel to the U.S. market. The agreements were subject to pre-acquisition notification and review by the Federal Trade Commission, the companies said.
Last June, Immunex and IVAX announced plans for collaboration. Both companies were developing paclitaxel injection products to compete with Taxol in the U.S.
In recently completed transactions, IVAX acquired the Immunex ANDA for paclitaxel injection and the Immunex inventories of bulk paclitaxel.
If the Immunex ANDA reaches the market, IVAX will pay Immunex royalties based on the net sales of this generic paclitaxel injection. In addition, at IVAX's request, Immunex will help IVAX promote the generic paclitaxel product using its oncology sales force, earning additional fees for this effort.
Both Immunex and IVAX have filed ANDAs requesting FDA approval of generic paclitaxel products and claimed in their ANDAs that certain use patents held by Bristol-Myers Squibb relating to Taxol are invalid or not infringed by their products. Bristol-Myers Squibb has challenged this certification, filing lawsuits for infringement of such patents. IVAX has filed a counterclaim against Bristol-Myers Squibb to invalidate the patents, and has asserted claims against them for violations of federal anti-trust laws and unfair competition. As part of the agreements, IVAX will direct the defense of both lawsuits, and Immunex will reimburse IVAX for a percentage of its paclitaxel patent litigation expenses relating to the ANDA applications.
In a related development, Hauser of Boulder, CO, said it has entered into a non-exclusive agreement with Immunex, under which Hauser will supply bulk paclitaxel to Immunex and IVAX. Hauser said it has terminated its 1994 supply agreement with American Cyanamid Co. Hauser announced it has severed the exclusivity portion of its relationship with Yew Tree Pharmaceuticals for the supply of bulk paclitaxel. Hauser will continue to supply bulk paclitaxel to Yew Tree Pharmaceuticals for its product Yewtaxan, but also will be allowed to supply other companies for marketing in Europe.
NIH, DuPont Reach Agreement on Research Use of Cre-lox
The National Institutes of Health (NIH), the Jackson Laboratory, and DuPont Pharmaceuticals Co. announced that they have signed agreements on the use of DuPont's proprietary Cre-lox technology. The agreements resolve longstanding issues of access by academia to commercially owned technology.
Now the NIH and DuPont have a mutually agreeable means for Cre-lox technology to be used in research conducted by and/or supported by the NIH, without compromising DuPont's ability to receive appropriate value from commercial applications of the technology, the company said. Officials at the NIH, Jackson Laboratory, and DuPont said the agreement that involves a commercially owned, enabling research tool may serve as a model for similar agreements between academic institutions and commercial research organizations.
The announcement of the agreement was made by NIH Director Harold Varmus during his keynote address at the meeting on Cancer Genetics and Tumor Suppressor Genes at Cold Spring Harbor Laboratory.
The Cre-lox technology involves site-specific recombination of DNA using the cre gene and lox sites. Its usefulness in basic medical research is widely recognized. Cre-lox site-directed recombination has shown great utility in improving existing gene knockout technology, particularly when used in genetically manipulated mouse models.
"The agreement between DuPont and the NIH is a milestone in the cooperative relationship between academia and industry," Varmus said. "It will allow science to continue to move forward freely as it uses a valuable commercially owned research tool for the benefit of medicine and the public." The agreement streamlines and clarifies the manner in which the Cre-lox technology is made available to academic research laboratories. "DuPont Pharmaceuticals is committed to wide dissemination of this valuable technology to the academic community," said Paul Friedman, President of DuPont Pharmaceuticals Research Laboratories. "We will continue to provide, at no cost, the Cre-lox technology to academic laboratories for research uses and will allow unencumbered use and transfer of this technology among researchers at not-for-profit institutions."
The agreements distinguish between academic and commercial uses of the technology. DuPont has agreed to make the technology available without cost to NIH researchers and grantee institutions for non-commercial purposes. Researchers affiliated with the NIH will be able to disseminate Cre-lox materials to other academic laboratories and investigators for academic research under a Material Transfer Agreement. The recipient non-profit institutions need an academic license with DuPont to transfer the NIH materials or to practice further under the Cre-lox patents. Discoveries made within the academic realm through use of the Cre-lox technology will not be subject to any payments to DuPont so long as the discovery is made outside of any benefit accruing to a commercial entity.
Under the agreement, DuPont and NIH recognize that academic institutions may want to transfer materials containing the Cre-lox technology to commercial entities. Such transfer of materials requires the commercial entity to pay a reasonable transfer fee and obtain a commercial research license. The current agreement does not cover agricultural applications, alteration of mouse embryonic stem cells for the purpose of preparing a library, and commercial uses. The agreement imposes no limitations on scientific publications. The full text of the agreement is available at http://www.nih.gov/od/ott
To further foster widespread use of and access to Cre-lox materials, including genetically manipulated mice, an agreement has been reached with The Jackson Laboratory to receive, breed and distribute animals that contain this technology to both academic and commercial parties.
FDA Approves Gemzar Use in Advanced Lung Cancer
Eli Lilly and Co. of Indianapolis said the FDA has approved the company's anticancer agent Gemzar (gemcitabine HCl) for use in combination with cisplatin for first-line treatment of inoperable, locally advanced, or metastatic non-small cell lung cancer (NSCLC). The FDA's decision to approve Gemzar for NSCLC was based in part on results from a large phase III trial that showed a statistically significant survival advantage among patients who received the combination regimen of Gemzar and cisplatin compared with patients who received cisplatin alone.
Clinical investigators conducted two randomized, multicenter clinical trials evaluating Gemzar in combination with cisplatin. A phase III study, which evaluated 522 patients with advanced NSCLC at 39 sites in North America and Europe, compared patient survival between Gemzar-cisplatin and cisplatin alone. Results of the study showed that patients had a significantly higher one-year survival probability with the combination Gemzar-cisplatin than cisplatin alone, 39% versus 28%, respectively. Patients who received Gemzar plus cisplatin had a significantly higher tumor response rate than patients who received cisplatin alone, 26% versus 10%, respectively. The median time to disease progression was significantly longer for patients treated with Gemzar plus cisplatin compared with patients treated with cisplatin alone, 5.2 months versus 3.7 months, respectively.
Another multicenter, randomized study compared Gemzar plus cisplatin against cisplatin plus etoposide in 135 patients with advanced disease. The tumor response rate was significantly higher in the Gemzar plus cisplatin group compared with the cisplatin plus etoposide group, 33% versus 14%, respectively, the company said. The median time to disease progression was significantly longer for patients treated with Gemzar plus cisplatin compared with patients who received cisplatin-etoposide, 5.0 months versus 4.1 months. While the trial was not designed to show a survival advantage, results showed that the one-year survival probability was comparable between both treatment groups.
In the combination studies with Gemzar-cisplatin, myelosuppression, a reduction in blood cell counts, was the most common, severe side effect reported.
FDA Approves Zoladex Use in Local Prostate Cancer
Zeneca Pharmaceuticals of Wilmington, DE, received FDA approval for Zoladex (goserelin acetate implant) in combination with the antiandrogen flutamide prior to and during radiation therapy for the management of prostate cancer locally confined to the prostate gland. The indication makes Zoladex the first and only hormonal treatment in its class (LHRH-A) approved for combination treatment against early stages of prostate cancer, the company said.
The approval of the SNDA, which includes both the 3.6 mg monthly depot and 10.8 mg three-month depot formulations, marks a broadening of the existing indication for the palliative treatment of advanced prostate cancer.
The effects of Zoladex in combination with flutamide plus radiation therapy were studied in 466 patients (Group 1: 231 Zoladex + flutamide + radiation; Group 2: 235 radiation alone) with locally confined prostate cancer, the company said. Results of the multicenter, controlled clinical trial, conducted by the Radiation Therapy Oncology Group, showed that disease-free survival was significantly increased in Group 1 compared to Group 2 (4.4 years versus 2.6 years, respectively; p < 0.001).
Inclusion of normal PSA level as a criterion to measure disease-free survival resulted in significantly increased disease-free survival in patients receiving combination therapy (2.7 years versus 1.5 years; p < 0.001). Group 1 had a significantly lower rate of local failure compared to Group 2 at four years (16% versus 33%, respectively; p < 0.001). Combination therapy also resulted in a trend toward reduction in distant spread of disease (27% versus 36% at four years, p = 0.058).
Zoladex is a luteinizing hormone-releasing hormone analog (LHRH-A), also known as gonadotropin-releasing hormone (GnRH) agonist. Zoladex offers a nonsurgical alternative to orchiectomy with similar effectiveness, the company said.
Administered via injection into the fat just below the skin of the abdomen, the biodegradable implant, or "depot," slowly dissolves, delivering the drug continuously over a period of four weeks (3.6 mg depot) or three months (10.8 mg depot). Zoladex has been established as primary endocrine therapy in clinical trials worldwide involving more than 8,200 cancer patients. Hot flashes are the most frequently reported side effect with Zoladex. Unspecified cancer-related pain and lower urinary tract symptoms were also common.
The one-month Zoladex 3.6 mg depot is also indicated for the treatment of advanced breast cancer in premenopausal and perimenopausal women, as well as for the treatment of endometriosis and as an endometrial thinning agent prior to endometrial ablation for dysfunctional uterine bleeding.
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