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QUESTIONS SUBMITTED BY THE SUBCOMMITTEE

DELAYED OBLIGATION OF FUNDS

Question. Dr. Broder, I noticed that of the funds you have requested for 1992, $63,446,000 would not be available until September 19 or with less than two weeks remaining in the fiscal year.

For each of the NIH institutes, a similar proposal is made resulting in $400,000,000 of the NIH $548,212,000 increase delayed until the end of the fiscal year. I am sure that OMB has proposed this as a gimmick to keep outlays down, and the Congress may well need to follow suit ... but what operational difficulties will this create for the Cancer Institute?

Answer. The delay in releasing approximately $63 million of FY 1992 funds could impose some operational difficulties on the Institute. Over the years the NCI has been very conscious of balancing its workload for both grant and contract awards among each of the quarters of the year. This minimized excessively heavy peak periods for the processing of grants and contracts. Without such an endeavor, staffing levels would need to be at a level sufficient to handle peak times.

With the knowledge that the funds would be released on September 19, 1992, the program and administrative staff could complete the negotiation phases with recipient institutions prior to September 19th. They would delay the actual signing of legal documentation until funds are received from OMB through the apportionment process. It is conceivable that delays in processing requirements could surface at this time. Given that there are only 11 days in the balance of the fiscal year, this could compromise our ability to make complete awards. However, we of course would prefer to have these funds available under these circumstances than not at all.

GENE THERAPY EXPERIMENT

Question. Last September at the Clinical Center, an historic gene therapy experiment was begun on a little girl with a previously incurable and deadly disease that shuts down the immune system.

I understand that the experiment has gone well, and the little girl now has a nearly normal immune system. Could you describe the therapy for the Committee and its potential for curing other diseases?

Answer. In 1989, NIH researchers from the National Cancer Institute and the National Heart, Lung, and Blood Institute obtained permission from 13 different review committees, including the Food and Drug Administration, to perform one of the most important clinical studies of our time, the first human trial of gene transfer therapy. The gene introduced into the cells was the neomycin resistance gene, chosen mainly to provide a marker by which tumor infiltrating lymphocyte (TIL) cells could be tracked throughout the body. This trial has been completed and has

demonstrated the safety and feasibility of this technique. The genetically modified TIL cells were tracked in the blood stream for up to 120 days and isolated from the tumor as long as 60 days following infusion.

Gene transfer therapy is now being pursued simultaneously on two fronts: insertion of genes into TIL cells to enhance their tumor killing capabilities as well as insertion of normally functioning genes into cells obtained from individuals with diseases caused by specific genetic deficiencies or abnormalities. Beginning in January of this year, cancer patients have been treated with TIL cells altered in the laboratory to include the gene for tumor necrosis factor (TNF), a naturally occurring substance that stimulates the tumor fighting capabilities of TIL cells. These patients are being closely monitored to see if these genetically modified TIL cells are effective at eradicating their tumors.

In the Spring of 1990, a young girl with an immunodeficiency disease called severe combined immunodeficiency caused by an inherited lack of the adenosine deaminase (ADA) enzyme received normal lymphocytes that had been taken from her body, genetically altered in the laboratory to contain a normal ADA gene, and given back intravenously to the girl. The girl has been followed for more than nine months and now has normal ADA levels as well as a normal immune system.

Gene transfer therapy has tremendous implications for diseases caused by specific genetic abnormalities, many of which are currently fatal. These include inborn errors of metabolism, which cause significant disability and death in infancy, as well as acquired genetic defects which cause diseases such as diabetes in adolescence or adulthood. Although treatments exist for many of these disorders, these treatments are aimed mainly at the control of the end manifestations of the disease. Gene transfer therapy has the potential to address the very cause of these diseases, providing the hope that, for the first time, we may be able to cure individuals stricken with these devastating diseases. Gene transfer therapy holds great potential for diseases such as sickle cell anemia, cystic fibrosis, thalassemia, and glycogen storage diseases, which exact a tremendous toll on the health of Americans every year.

ETHICAL CONSIDERATIONS OF GENE THERAPY EXPERIMENTS

Question. Dr. Broder, as you know better than I do, gene therapy is manipulating the fundamental blueprint of a human being which of course could and does raise ethical questions. What level of review do you believe is necessary for gene therapy experiments?

Answer. An extensive review process has been set up to review gene therapy experiments. All efforts at gene therapy must receive approval from the following review groups before they can begin:

Institutional clinical Research Committee
Institutional Biosafety Committee (that deals with
recombinant DNA research)

The National Recombinant DNA Advisory Committee (RAC) and its

Gene Therapy Subcommittee
The Food and Drug Administration

Each of these review groups contains scientists, clinicians, ethicists and lay people.

Finally, before any attempts at gene therapy can begin, final approval must be received from the Director of the National Institutes of Health.

This review process is very detailed in order to provide careful consideration not only to the importance of the science but also to issues of patient safety.

NON-CONVENTIONAL CANCER TREATMENTS

Question. Dr. Broder, I want to thank you for visiting with Congressman Berkly Bedel and discussing with him non-conventional treatments. How can the Congress be sure that we are giving adequate attention to non-conventional treatments, some of which turn out to become mainstream? For example, I understand radiation therapy was regarded as radical and not recommended for many years, but now it is common practice.

Answer. As noted in the Office of Technology Assessment's (OTA) report on Unconventional Cancer Treatments, one of the greatest impediments to the evaluation of these approaches is the lack of interpretable scientific data. To address this, the NCI has placed responsibility for the evaluation of Unconventional Cancer Treatments (UCTs) in the Investigational Drug Branch of the Cancer Therapy Evaluation Program which is also responsible for the early clinical development of "conventional" approaches (e.g., chemotherapy and biological response modifiers) for the treatment of cancer. The Chief of this Branch, Dr. Michael J. Hawkins, recently attended the Fourth Annual Lloyd Symington Foundation Conference on New Directions in Cancer Care at the request of Dr. Michael Lerner, a Special Consultant to the OTA for their report on UCTs. At this meeting, Dr. Hawkins discussed the type of clinical data that would be viewed as scientifically meaningful and proposed some approaches which could be used to generate such data. These data, if positive, would warrant the conduct of confirmatory trials by the NCI and/or could be cited in investigator-initiated grant applications. As a result of this meeting and Dr. Hawkins' presentations, discussions on how to best generate such pilot data have begun with proponents of psychospiritual and dietary approaches to the treatment of cancer. While remaining open to novel or unconventional ideas, it is important to stress that the NCI must adhere to sound scientific methods. Moreover, NCI must provide a level playing field to ensure that all individuals who make claims for new cancer cures are held to the same standards of proof.

In response to one of the Options proposed in the OTA report, the NCI is in the process of developing guidelines for the preparation of "best case series." We anticipate that this document will be available not later than May, 1991. However,

there are significant practical problems and scientific limitations associated with the preparation and interpretation of these retrospective analyses. The NCI feels it is far preferable to generate new data in small pilot studies and will provide guidelines for the conduct of such studies in this document as well. These studies typically require fewer than 100 patients. For most of the UCTs, uninterpretable data have already been collected on many more patients who have, unfortunately, received the UCTs in an uncontrolled fashion. This pilot study approach has been used in the past with success to identify both promising and ineffective UCTs. Based on a small (65 patient) randomized pilot study which demonstrated increased survival in patients receiving hydrazine sulfate, the NCI initiated three large scale confirmatory clinical trials in the Cooperative Groups. In contrast, similar studies of Laetrile and Vitamin C were negative. It is worth stressing that the NCI is actively studying Vitamin C as a possible chemoprevention agents in various settings.

CANCER INCIDENCE RATES

Question. Dr. Broder, I have a chart that was included in the Cancer By-Pass budget that shows the incidence rates for the 24 major types of cancer. Fifteen of these cancers are showing increasing incidence rates between the period 1973 to 1987. Are we making progress in the war on cancer?

Answer. Yes, there are indications that improvements in cancer rates have occurred, we have good news and bad news in our statistics.

Let me begin first with the good news. In persons under 65 we show a continuing decline in cancer mortality, a total of 4.3 percent from 1973 to 1988. We believe the decline is due to two broad factors. First, we cite the effects of cancer prevention and early detection regimens, specifically, reduction in smoking, an increase in early detection of breast cancer among younger women, an increase in the percentage of women undergoing cervical cancer screening, and, perhaps, the impact of a changing diet. Secondly, we believe there has been a general improvement in treatment and early detection and that these advances have been applied to a fuller extent in the younger population group.

Many cancers show startling reductions in mortality for persons under age 65. For example, as shown in Table 1, childhood cancers have declined 36 percent, Hodgkin's disease declined 54 percent, bladder cancer 32 percent, colorectal cancer 16 percent, stomach cancer down 30 percent, breast cancer in women under 50 declined 11 percent, and oral cancer fell by 21 percent. We even see a change in pancreatic cancer, one of the deadliest of all cancers which for all persons under 65, has fallen 13 percent. As a direct result of changes in smoking habits, the net change in lung cancer mortality among men since 1973 has been an increase of only one-half of one percent over the entire period. The figure for females is a startling 67 percent (with a corresponding figure for those over age 65 of 166 percent.)

Other increases for persons under age 65 include melanoma up 16 percent, breast cancer in women over 50 increased 4.8 percent,

esophageal cancer increased by 5 percent, multiple myeloma up 11 percent,

In persons over 65 the net change in mortality for all cancers combined is an increase of 12.9 percent over the period 1973 to 1988. Reviewing the figures in Table 2, we can see that fewer cancers show decreases for persons over 65. Some of the cancer showing decreases for persons 65 and over include: oral cancer down 15 percent, stomach down 33 percent, colorectal cancers down nine percent, cervical cancer down 42 percent, and Hodgkin's disease down 51 percent,

Cancers showing increases for persons 65 and above include: non-Hodgkin's lymphoma up 41 percent, brain cancer up 59 percent, melanoma also up 59 percent, and lung cancer for males and females combined up 55 percent. As I noted lung cancer among females 65 and over is up 166 percent while the figure for males is 32 percent, reflecting the decrease in smoking among males, the smaller decrease among females and the fact that females began to smoke somewhat later than their male counterparts,

The challenge posed by these age-specific statistics is obvious: the clear and unequivocal progress seen among persons under 65 must be extended to a greater extent to those over 65, Some of the increases among older Americans are well understood, while others are baffling, For example, the increase in melanoma is strongly believed to be due to increased ultraviolet radiation, in particular, sun exposure. The increase in breast cancer mortality, particularly in the face of improved treatment, may be due to changes in diet. Changes in other risk factors have been suggested but at this point in time do not correlate with the mortality increase. The increase in brain cancer is most likely due to improved methods of identifying causes of death. In other words the true rate of death from brain cancer has not changed, but the frequency at which we diagnose the cause of death correctly has improved because of new technology such as the CAT scan, and improved access to health care through Medicare, Another baffling change is in non-Hodgkin's lymphoma with an increase of 41 percent among persons over age 65. An increase of two percent is due primarily to AIDS which makes its victims more susceptible to non-Hodgkin's lymphoma and to Kaposi's sarcoma.

Blacks bear a disproportionate burden of cancer, a burden marked by increasing mortality rates for many cancer sites in sharp contrast to more favorable trends among whites. The mortality rate among blacks is 213.0 deaths per 100,000 persons in contrast to 168.5 among whitesThe sex-specific rates show that black males have a mortality rate of 293.4, 38 percent higher than the rate of 213.1 for white males. The figures for females are 158.5 deaths per 100,000 persons for black females, a figure that is 14 percent higher than the rate of 139.0 deaths per 100,000 for white females. The trend figures show an increase in mortality for whites of 5.3 percent from 1973 to 1988 while the corresponding figure for blacks is 9.6 percent. In other words, not only are the mortality rates higher among blacks, the rate of change is greater among blacks. In a sense the cancer mortality gap between blacks and whites has widened.

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