TAXOL

Question. Dr Broder, we have been hearing a lot about a new drug called TAXOL that is effective in treating ovarian cancer. Can you tell us more about this promising new therapy?

Answer. Taxol is a new plant derived antineoplastic agent isolated from the western yew, taxus brevifolia. It is a complex alkaloid ester which has unusual interactions with mammalian tubulin. Taxol markedly enhances all aspects of tubulin polymerization including initiation and elongation, and the microtubules formed are more stable to depolymerization. Currently, the only source of taxol is from the bark of the western yew tree and because of low yield on isolation, large numbers of trees must be harvested. For this reason, drug supply is limited. As I noted earlier when we discussed taxol as a treatment for ovarian cancer, several approaches have been taken to relieve this situation, including identification of new sources of yew trees, identification of renewable species of taxus, and the development of semi-synthetic techniques. In order to increase drug supply, a Cooperative Research and Development Agreement (CRADA) for the production of taxol has been established between the NCI and Bristol-Myers Squibb.

Over the past year, clinical trials have demonstrated that taxol has significant activity against recurrent ovarian cancer and has promising activity in recurrent breast cancer in 25 previously treated patients (a total of 48 percent complete plus partial remissions) and non-small lung cancers. At present, the NCI has active Phase I and II studies of taxol in ovarian, gastric, breast, non-small lung cancer, cervical, colon, and prostate cancers. Because of this response rate, the Medicine Branch in NCI's intramural program is planning an up-front regimen in ovarian cancer with taxol, cisplatin, cyclophosphamide and GCSF a colony stimulating factor. The Gynecologic Oncology Cooperative Group, a member of the NCI Clinical Trial Program, has already started an up-front study with taxol in suboptimally debulked ovarian cancer. In this study, patients are randomized to receive either cyclophosphamide/cisplatin or taxol/cisplatin; 66 patients have been entered with a goal of 120-180. The NCI also plans a confirmatory trial in breast cancer that will be starting in the next several months at Memorial Sloan Kettering. Additionally, a combination trial of taxol, adriamycin, and GM-CSF in metastatic breast cancer is slated to start soon in the Medicine Branch, NCI. Taxol represents a major advance in chemotherapy. However, obtaining adequate supplies of this drug will remain a formidable problem.

QUESTIONS SUBMITTTED BY SENATOR DALE BUMPERS

PROGRAM PROJECT GRANTS

Question. Program project grants are particularly important because they provide an opportunity to integrate basic and clinical research teams. I understand that NCI may be considering breaking up P01s and encouraging PO1-supported investigators to apply upon renewal for individual investigator awards. This would result in a greater number of total awards.

Aren't Pols particularly important in translating laboratory findings into clinical applications?

Answer. By supporting related basic and clinical research projects within a single P01, program project grants provide a useful framework to encourage collaboration between basic and clinical researchers. When used in this way, they provide new opportunities to facilitate translation of basic laboratory findings to clinical application. The NCI will continue to support with enthusiasm P01s which promote these collaborative efforts.

It is important to note that POls are not the only vehicle for moving basic research findings quickly into clinical applications. Several other NCI mechanisms such as the Clinical Cooperative Groups and Cancer Centers are valuable and necessary to this effort. Within the Cancer Prevention and Control Program, many community outreach efforts have been developed which permit the translation of basic and clinical research findings into a community setting; the Community Clinical Oncology Program, through over 50 awards, is one of the most notable.

The revolution in biomedical research over the past few years has made it possible to move basic research findings from the laboratory to the bedside. Developing innovative ways to facilitate such a movement is one of the challenges facing the NCI. Program projects are among the weapons in the armamentarium which assist in this effort.

Question. How can NCI defend dismantling the P01 mechanism to play a numbers game?

Answer. The NCI is not reviewing the option to disaggregate Program Projects (PO1s) solely to meet a requirement to support a specific number of competing grants. We are making a programmatic evaluation to assure that research projects being supported within a P01 are part of a cohesive entity that is the most effective way to conduct the research. Each Program Project, on the average, supports the equivalent of five to seven independent investigatorinitiated grants. There may be instances in which an individual project does not require the synergism provided by a P01 and would be as effective if supported as an independent research grant (R01) rather than as a sub-project within a P01. NCI would recommend that in such cases projects become independent R01 grants during their competitive cycles.

TRAINING OF PHYSICIAN SCIENTISTS

Question. NIH and the scientific community are well aware of the shortage of well-trained physician scientists. Despite this recognition, the number of awards from the NCI Research Career Program training mechanisms particularly attractive to physicians has not increased over the past decade. The By-Pass budget calls for a doubling of these awards over the next two years. How will the President's budget proposal affect this goal?

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Answer. The NCI Research Career Program is the primary way in which medical doctors who have developed clinical skills can receive the training necessary to pursue effective research

careers. By combining their clinical and research skills, these specially trained individuals become critical links for

translating basic scientific discoveries into clinical research that ultimately benefits patients and reduces cancer incidence and mortality.

The By-Pass Budget includes a request level of $13 million. These resources would permit NCI to provide significantly greater incentives for young physicians to pursue research careers in cancer. The President's Budget of $8.8 million will permit maintenance of the existing program.

GRANT REVIEW OF CLINICAL STUDIES

Question. I understand physician scientists often have a tough time competing for research grants, in part because the study sections to which their proposed projects are assigned have limited expertise in clinical research. How does NCI, in conjunction with the NIH Division of Research Grants, intend to address problems related to grant review of clinical studies?

Answer. The NCI has reached an agreement with the Division of Research Grants (DRG) whereby an expansion of committee membership for review of clinically oriented research grants will be made concomitantly with an anticipated increase in investigator-initiated research project applications. The Experimental Therapeutics 2 Study Section, which reviews the majority of such applications, will add three new members with clinical qualifications. To further increase the number of clinical reviewers, NCI and DRG staff also have nominated additional individuals, with clinical qualifications for service in the NIH Reviewers' Reserve, where they may be called upon to serve as full voting members of chartered Initial Review Groups, as needed, to review clinical research projects. Over the longer term, as the volume of clinical research applications increases, the Division of Research Grants will consider the chartering of an Initial Review Group specifically to review clinical studies of cancer research.

REIMBURSEMENT OF PATIENT CARE COSTS

Question. As third-party payers including Medicare continue to tighten cost controls, medical specialty organizations have reported increased difficulty getting reimbursement for patient care costs associated with so-called "experimental" treatments. In your testimony before this subcommittee in 1989, you made very clear that NCI "strongly supports the idea that treatment with investigational therapy in scientifically meritorious clinical trials is standard therapy for cancer patients for whom no reliable curative therapy exists." Are NCI grantees continuing to encounter problems in securing reimbursement for the patient care costs associated with clinical research?

Answer. Investigators continue to confront varying degrees of difficulty in obtaining coverage for the patient care costs associated with NCI-sponsored clinical trials. It is difficult to quantify the problems due to the decentralization of the insurance industry. Coverage decisions vary from one geographic location to another and from one insurer to another. However, in a recent

survey of 200 oncologists which was released March 7, 1991, 41% of the physicians reported that reimbursement for clinical trials has declined in the past year.

Documented examples of reimbursement issues regarding patient care costs which have occurred in important areas of research include: first, denials of a Phase II trial of taxol which was conducted at Johns Hopkins University in women with ovarian carcinoma refractory to platinum; second, denials of Group C agents despite a statement of coverage by Medicare; third, denials of bone marrow transplant for Stage IV breast cancer in women who are participating in peer reviewed, scientifically valid clinical trials.

NCI continues to support reimbursement for patients enrolled in scientifically meritorious clinical trials and to this end, NCI is actively working to promote a dialogue with insurers to better meet our joint goal of providing more effective treatment for cancer patients. NCI believes that the recent initiative of Blue Cross-Blue Shield supporting the patient care costs for their subscribers enrolled in NCI-sponsored High-Dose Chemotherapy/ Autologous Bone Marrow Transplantation (HDC/ABMT) trials is a step in that direction.

Question. If so, how will this impede scientific progress?

Answer. Continued reimbursement denials will have a profound effect on the development of new therapies. If insurers will not cover the patient care costs of a trial, accrual to that study will be slowed and completion will take much longer than projected. Restricted reimbursements may also limit the number of trials that can be done at excellent cancer research institutions. Both of these constraints will ultimately delay the identification of new, efficacious therapy. A restrictive system will potentially evolve in which only those who can afford to pay will have access to the new, innovative therapies which cancer clinical trials offer.

QUESTIONS SUBMITTTED BY SENATOR ARLEN SPECTER

HEALTH EFFECTS OF HIGH VOLTAGE POWER LINES

Question. Dr. Broder, the residents of South Scranton, Pennsylvania are deeply concerned over the health effects of high voltage power lines which run through their community. Community residents report an elevated incidence of cancer. What message should I bring back to the people of South Scranton regarding this serious matter?

Answer. As you may know, power transmission lines produce electromagnetic fields (EMF). The energy from these fields is in the form of extremely-low-frequency (ELF) waves. These waves are also produced by other devices, such as household appliances and electric blankets. Unlike extremely-high-frequency waves, such as x-rays and ultraviolet light, ELF waves have not been proven to

cause cancer.