Part 2 of 7
The November NACC Meeting
On November 18, 1964, a main item on the agenda of the NACC meeting was a review of the total Field Studies Area. Documentation had been supplied to Council members prior to the meeting, including a listing of all contracts (“Field Studies Area Program Presentation to the National Advisory Cancer Council,” Dr. Paul Kotin to the NACC, November 18, 1964). Paul Kotin, the head of the Field Studies Area, made the presentation. Included in this review was the program of the Viruses Research Resources Branch (headed by Bob Stevenson), which by this time had been moved into the Field Studies Area. About one-quarter of the Field Studies funds were in the VRRB. VRRB contract monies totaled about $2.274 million; the Field Studies total was $9.334 million. Of the VRRB funds, 53% were in Cell Culture and Tissue Materials, 30% in Laboratory Animals, 10% in Cancer Virology, and 7% in Human Cancer Virus work. Staff of the Field Studies Area would be involved in four of the eight Program Segments outlined in the presentation before the NACC at the October 12 and 13 meeting. The expanding Special Viruses Leukemia Program consisted of four parts: resources and logistics; testing and monitoring; epidemiology; and biohazards control and containment. The NACC endorsed the projected Program.
1965
By the end of 1964 the pace of research findings had picked up, and, with the new monies for the Special Virus Leukemia Program, greater progress still would be made. In addition to the techniques of virus identification by tumorgenicity and infectivity and the demonstration of type-C virus particles by electron microscopy, immunofluorescence studies and complement fixation investigations were ready for further development. These developments would require production of larger amounts of reagents, especially large amounts of better quantifying antisera of various types - and testing and monitoring procedures - and other resources such as specimens of human and animal sera and tissues, including acute leukemia specimens; tissue cultures of various cell lines; several species of animals and animal model systems; vaccines that produced protection against animal tumor viruses (polyoma, Rauscher, and Friend viruses); production of platelets and granulocytes by special centrifugation techniques for transfusion to leukemia patients to combat bleeding and infection; and additional considerations on biohazards control and containment. Considerable confusion still existed about the relationships of the members of the four families that contained tumor-causing viruses (Papovaviruses; Adenoviruses; Poxviruses; and the Myxovirus-Like Group), partly because some viruses, like the Rous virus, were incomplete and required helper viruses for the Rous virus to reproduce. In none of these groups is every member known or suspected to be tumorgenic. Also, the animal test systems themselves were contaminated. Concerning epidemiologic patterns of tumor virus infection, there was no common denominator. Polyoma virus spreads by contact with infected urine, fowl leukosis and probably mouse leukemia viruses are transmitted transovarially, or possibly in the latter case, transuterinely; the mouse mammary agent and laboratory strains of mouse leukemia viruses are milk borne; the mammary agent can also be transmitted vertically; fibroma virus is mosquito borne; and wart viruses are probably spread by fomites (see Wally P. Rowe, “A Survey of the Tumor Virus Problems from an Epidemiological Standpoint,” Cancer Research, vol. 25, No. 8, pp. 1277-1282, September (1965)).
Knowledge of how these viruses spread is essential for future epidemiology investigations. Some of the research findings at this stage at the molecular level would have far-reaching implications for understanding aspects of molecular biology and for the development of biotechnology. A key finding was evidence of persistence of the viral genome in virus-induced tumor cells, often with specific modification of the cells due to partial expression of the genome. Also at this stage, at the molecular level, Maurice Green at St. Louis University, an active participant in the Special Virus Leukemia Program, was demonstrating differences between the DNAs of the non-tumorgenic Types 2 and 4 adenoviruses and the tumorgenic Types 12 and 18. DNAs of types 2 and 4 have 56-57% guanine-cytosine while those of Types 12 and 18 have 48-49% guanine-cytosine. These findings suggest that the tumorgenic adenoviruses may have evolved from the nontumorgenic viruses through loss of a piece of DNA rich in guanine-cytosine. It is also possible that tumorgenic and nontumorgenic adenoviruses, although possessing in common certain properties which lead to their classification as a family, may be genetically unrelated. Green also observed that the four DNA-containing viruses that produce tumors in mammals, viz., adenovirus Types 12 and 18, the polyoma virus, and the papilloma virus, have similar base compositions. It also seemed possible that the tumorgenic potential of a virus might depend on the existence in its DNA of a region homologous in structure to a region of DNA of the host cell. If such a segment of host cell DNA combines with, or is replaced by, the tumor virus DNA, the functions controlled by this region of host cell DNA would come under the control of the tumor virus DNA; i.e., the end result might be expressed as a take-over of the control of cell division (See Ed Lennette, “Formal Discussion of a Survey of the Tumor Virus Problem from an Epidemiological Standpoint,” Cancer Research, Vol. 25, No. 5, pp. 1286-1288, September (1965)). [These investigations were the forerunners of the identifications of gene sequences of oncogenes - 1969, and proto-oncogenes - 1973]. Also by 1965 important advances in chemotherapy of leukemic children had been achieved. Combination of four drugs (vincristine, amethopterin, 6-mercaptopurine, and prednisone) given simultaneously was producing long-term remissions or possibly cures. With these four drugs the desired chemotherapeutic effects were cumulative while the adverse toxic effects were not, thus allowing increased doses for treatment without increased toxicity. The transfusion of platelets and granulocytes and the placement of patients in a “life island” with a controlled “germ-free” environment reduced deaths from bacterial and fungal infections, a serious problem for patients whose bone marrows and immune systems were damaged by the chemotherapeutic drugs. Money from the Special Virus Leukemia Program helped fund therapy parts of the Program.
Working Group Meetings
Many meetings were held during the first half of 1965 with the working groups. Also many meetings were held with the Chairmen of the working groups with the OD Science/Management Team and among the Chairmen. Within dollar limits, priorities were hammered out, existing projects were modified, and new projects were proposed. Thus, these committees were not just reviewing proposals, but they were also engaged in planning new efforts in research and in the production of needed resources. In May, proposals were presented before the Scientific Directorate for approval or modification. Preliminary estimates were developed for additional Program efforts for Fiscal Year 1966. These actions were taken to meet the objectives in the Special Virus Leukemia Program. Attention was given to requirements of data flows and reporting, as well as scientific information and administrative and accounting requirements. By June 30, 1965, all planned projects were officially executed as research contracts. The NCI staff put forth unusual efforts to meet these tight deadlines.
Emergency High Hazard Facility
On February 1, 1965, a memorandum was sent to the Director, NIH, from Dr. Endicott requesting special construction authority to build an emergency high hazard facility on the NIH campus. This request was made because the various viruses being worked on were potentially dangerous to those investigators working with these viruses, and immediate action was needed to protect them. The Office of the Secretary, HEW, approved the request on April 12, 1965. The designation of the building as a temporary, emergency structure, which at that time was an appropriate designation, allowed progress on the actual construction to proceed at a much more rapid schedule than was usual to move through the morass of construction authorities and approvals. An amount of $2.8 million was reserved for construction in Fiscal Year 1966. Gordon Zubrod, Director of Intramural Research, and Bill Payne, Chairman of the Biohazards Control and Containment working group, developed the coordination of activities for this contract. Dr. Payne, other NCI scientists, and the Biohazards Control and Containment working group also developed requirements for a research and development contract in biohazards control and containment (to include the design, mockup, testing, fabrication, and installation of new equipment, instrumentation, procedures, etc.). After a meeting with potential contractors where the Program and the requirements of the contract were explained and questions were answered, the working group reviewed proposals from five potential contractors. On approval April 27, 1965, a contract was awarded for the first of five phases with a ceiling of $990,000 from 1965 funds. On authorization of the U.S. Congress for special construction, NCI contracts were awarded to universities for the construction of three buildings for studies of bovine leukemia and one building for studies of cat leukemia.
Special Virus Leukemia Program -- End of F. Y. 1965
With the end of Fiscal Year 1965 on June 30, 1965, the Science/Management Group sent on August 3 a summarizing memorandum to members of the working groups. Part of this memorandum follows:
In a span of approximately eight months, the chairmen and working group members have developed detailed program plans for their respective areas, and accomplished the difficult task of developing and reviewing numerous research projects which have been officially executed as 48 research contracts. As of the close of the books for fiscal year 1965, $9,932,000 of the $10,000,000 appropriated has been obligated. It is realized that the fast pace of activities required for this accomplishment has left insufficient time for working group members to acquire a detailed knowledge of the individual contracts developed by working groups other than their own.
Attachment I presents key information on each contract developed and implemented during the year. The contracts are listed by working groups to stay within the program structure of fiscal year 1965. It is hoped that this material will provide you with the necessary background information so that the tasks of developing new projects and modifying existing program elements can be performed against a complete knowledge of the total program.
There will be some attempt to establish a better distribution of contract renewal dates by fiscal year quarters so as to reduce the heavy concentration of contract reviews that usually takes place in the third and fourth quarters. If this can be practically accomplished, you will receive an updated list of contracts reflecting any changes in renewal date.
Attachment II presents a summary breakdown of the number of contracts and the amount of funds obligated by the working groups.
Attachment III is a summary report of both the scientific and administrative activities accomplished in the program for the time period September 1964 through June 1965.
Attachment IV presents a reiteration and discussion of the main underlying program assumption.
It became increasingly apparent during the year that areas of overlap between the functions of the working groups on Developmental Research, Production, and Resources and Logistics were resulting in an uneven degree of participation by these groups in the program and in confusion as to which group had the responsibility of soliciting, developing, reviewing, and requisite monitoring of various production type contracts. After several discussions with the chairmen of these groups, it seems desirable to effect the following changes:
Eliminate the working group of Production at this time and re-align its membership with the Developmental Research and Resources and Logistics group as follows:
ORIGINAL MEMBERSHIP OF PRODUCTION GROUP NEW ALIGNMENT
Dr. Robert Manaker, NCI (Chairman) Developmental Research
Dr. Robert Couch, NIAID Resources & Logistics
Dr. Paul Gerber, DBS Developmental Research
Dr. Leonard Hayflick, Wistar Institute Testing & Monitoring
Dr. Alice Moore, Sloan-Kettering Inst. Developmental Research
Dr. Timothy O’Conner, NCI Developmental Research
Dr. Alan Rabson, NCI Developmental Research
With the end of the activities of the Special Virus Leukemia Program within fiscal year 1965, Dr. Ray Bryan has resigned as Chairman of the Developmental Research Working Group, in order to devote full time to his heavy responsibilities as a senior program leader in the NCI. Dr. Robert Manaker has agreed to succeed Dr. Bryan as Chairman of the Developmental Research Working Group -- effective July 1, 1965. Dr. A.J. Dalton has agreed to continue as Vice-Chairman.
Attachment V presents a new list of the members of each working group and includes the above changes.
The memorandum concludes with the reassignment of four contracts to Resources & Logistics and one to Developmental Research. The 48 contracts were distributed among the Program Segments as follows: 11 ($2,163,724) -- Developmental Research; 5 ($1,547,847) -- Production; 10 ($2,279,165) -- Special Animal Leukemia Ecology Studies; 8 ($1,115,595) --Human Leukemia Therapy; 5 ($812,936) -- Testing & Monitoring; 4 ($357,129) -- Resources & Logistics; 1 ($31,000) -- Epidemiology; and 4 ($1,161,851) -- Biohazards Control & Containment. For Direct Operations (Personnel, Travel, Equipment, etc.), $462,741 was obligated (“Program Materials,” OD Science/Management Team to Members of Working Groups of the Special-Virus Leukemia, August 3, 1965).
August 13-14, 1965 NACC Meeting
In July 1965 systems planning (the “Convergence Technique”) was applied to the Cancer Chemotherapy Program. Monitoring Points were added to the Decision Points on the systems networking chart for the Chemotherapy Program. It may be recalled that Decision Points require decisions that move the Program forward operationally toward the Objectives while the Monitoring Points require periodic considerations of whether the program itself needs modification. Monitoring Points were added to the systems network chart for viral oncology (SVLP).
At the August NACC meeting, an in depth review of the Cancer Chemotherapy Program was made; extensive information had been supplied to the Council members prior to the meeting. Dr. Endicott reviewed the history of the Program. Dr. Baker presented an extensive assessment of current scientific data in the cancer chemotherapy field and discussed the dynamics of the Program’s drug development activities through the various steps from acquisition of materials to use of drugs in the treatment of cancer patients. Dr. Zubrod presented program plans for a modified Chemotherapy Program, utilizing the systems planning chart developed with the “Convergence Technique.” He stressed the opportunities available for future improvements from the data and the management apparatus developed over the past decade. He discussed in detail the conceptual basis and theories underlying screening and clinical trials and described plans to incorporate cell kinetics into the Program base. From the minutes of the Council meeting: The Council expressed approval of the material presented and recommended that it be made available to the scientific community as a published monograph. [The material was published as: Zubrod, G., Schapartz, S., Leiter, J., Endicott, K., Carrese, L., and Baker, C., “The Chemotherapy Program of the National Cancer Institute: History, Analysis, and Plans” - Cancer Chemotherapy Reports, vol. 50, No. 7, pp. 348-540, (1966).] The Council also noted that this in-depth review was part of the regular, scheduled program review already planned before the action of the Wooldrige Committee. The Council then adopted the following motion:
“That the Council supports the general approach to cancer chemotherapy as outlined in the presentation of new program, including the lymphomas, leukemias, and breast cancers, with the recognition that a) this will have some impact on other parts of the program because of the need to maintain during the current year the total program at roughly the current level and b) as the program evolves during the coming year and as significant shifts of dollars are made between segments of the program, the Council would expect these shifts to be reported to it for such advisory inputs as it would wish to make in the evolution of the program during the coming and subsequent years.” Members of the Council at the meeting were: Walter J. Burdette, Salt Lake General Hospital; R. Lee Clark, M.D. Anderson Hospital and Tumor Institute; Philip P. Cohen, University of Wisconsin; Charles A. Evans, University of Washington; Sidney Farber, Harvard Medical School; Leo G. Rigler, University of California at Los Angeles; Philippe Shubik, The Chicago Medical School; Howard E. Skipper, Southern Research Institute; Joseph L. Melnick, Baylor University College of Medicine; Rubin H. Flocks, University of Iowa; and Lyndon E. Lee, Jr. (Ex Officio), Veterans Administration.
Considerable discussion was held on the role of the Council with respect to contracts and the Collaborative Research Programs. There was general agreement that the Council could not spend time reviewing every grant application, nor every contract. However, by law no grant could be awarded without approval of the Council; such was not the case with contracts. Some believed Council approval should be required for each contract as well. If this approval were instituted, it would have run in the face of general Government contracting policies and practices. One Council member considered the role of the Council in review of Collaborative Programs and the corresponding contracts “confusing” and “a vexatious and disturbing issue,” “an issue only because it was misunderstood.” He moved, and the Council agreed, “that the Director work out a simple system at every Council meeting, special or regular, of having a short review of the contracts which have been awarded since the last meeting, the areas in which they are, and any other information that would be important for the Council to know, so that the Council could then advise the Director in a better informed manner on planning and on the overall missions of the Cancer Institute.” The Director agreed to the motion and suggested that the motion be amended to “include not only a report of contracts which have been let in the intervening period but plans for invitations for proposals.” The amended motion was accepted.
On September 1, 1965, Dr. Shannon sent to Mr. Herman Downey, the Clerk of the Subcommittee of the Senate Committee on Appropriations, the material in the verbatim transcript and the minutes of the NACC meeting of August 13-14, 1965 [excerpted in the above two paragraphs]. This was done because Senator Hill, Chairman of the Senate Committee, had been told that the Chemotherapy Program was spending too much money and was not getting results and that the NCI was not providing the NACC information on the Chemotherapy Program or on contracts. The memorandum and the attachments were sent to Senator Hill to refute the charges.
Hearings Before Congressman Rogers Subcommittee
On September 1, 1965, Dr. Endicott, Dr. Baker and Mr. Learmouth appeared before the Rogers Subcommittee (2-6:15 p.m.) and were queried on a wide range of subjects. The Subcommittee staff displayed a lively interest in the evolution of the organization and programs of the NCI and particularly in those areas of applied and developmental research which were funded by contracts. They were especially interested in the planning functions and the charting techniques used for the Virus-Leukemia and Chemotherapy Programs. The Congressman expressed the view that support for free roving research through the grants activities was overdone and that expansion of applied and developmental research through contracts would provide society with practical answers to urgent problems at an earlier date. NCI was commended for consolidating the administration of grants and contracts. There were questions about the working relationships with the Bureau of State Services in cancer control and environmental carcinogenesis and about pros and cons of an annual authorization in lieu of the current open ended enabling legislation. Mr. Rogers seemed to favor annual authorization. An interesting set of questions were: (1) Would NCI be better off if it were an independent agency? (2) Would NIH be more effective if it were not a part of the Public Health Service? (3) Should the health function be given an independent departmental status? and (4) If the present department is maintained, should there be Under Secretaries for Health, for Education, and for Welfare? The following materials were supplied to the Subcommittee:
A. A list of accomplishments of the Cancer Chemotherapy Program.
B. A list of key research developments in carcinogenesis.
C. A general statement on cancer research developments since 1937.
D. A list of research grants and contracts for Fiscal Year 1964 classified in areas of cancer research.
E. A progress report on the first year’s operation of the Special Virus-Leukemia Program.
F. A memorandum dated November 5, 1965 to the NACC from the Associate Director for Program entitled “External Contract Research Centers,” which outlined a plan for a major, multipurpose research and development, contractor operated facility (Appearance before the Rogers Subcommittee, September 1, 1965,” Director, NCI, to Director, NIH, September 2, 1965).
Organization of NCI Extramural Research
As a follow-up to Dr. Endicott’s memorandum of July 15, 1965, on the reorganization of NCI, Dr. Phillip Waalkes, who succeeded Dr. Ralph Meader as Associate Director for Grants and Training, sent on October 25, 1965, a memorandum to the Staff, Extramural Research, NCI.
Dr. Meader retired after over 17 years service in NCI as head of the Grants and Training activities. Excerpts of the memorandum follow:
Although still awaiting final approval, it is planned to proceed as rapidly as possible to operate in accordance with the proposed new organization for Extramural Research which includes the Office of the Associate Director and five operating areas. Under this arrangement, within the Office of the Associate Director, Dr. Samuel Herman will act as Deputy Chief for Extramural Research. Mr. George Brandner, while retaining his position as Chief of the Grants and Research Contracts Operations Branch, is now part of the Office of the Associate Director.
The remaining four areas of Extramural Research, the individuals acting as heads, and the professional staff are as follows:
1. Program Review and Evaluation - Dr. Robert Greenfield.
Working with Dr. Greenfield, the professional staff includes Dr. Nadkarni and Dr. Lauri Luoto.
2. Special Programs Branch - Dr. William Walter.
Tentatively, Dr. Carl Hansen, Jr. has been assigned to work in this branch.
3. Awards Review and Technical Administration Branch - Dr. O. Malcolm Ray.
Professional staff assignments include Dr. Arthur Skipper and Dr. Ruth Lyman.
4. Cancer Therapy Evaluation Center - Dr. Margaret Sloan.
Working with Dr. Sloan will be all the professional staff who were members of the Clinical Branch of Collaborative Research (“Organization of the Extramural Research Division of NCI,” Associate Director for Grants and Training, NCI, to Staff, Extramural Research, NCI, October 25, 1965).
Ethical and Moral Aspects of Clinical Investigations
NIH began a new review of ethical and moral issues related to clinical investigation in the Fall of 1965, well before the subject became prominent with the laity. When the Clinical Center was established in 1955, guidelines were formulated that aimed at ensuring the safety and welfare of patients participating in clinical investigations. Dr. Jack Masur, the first Director of the Center, always insisted that the patient’s welfare should always take precedence over the needs of the research. A committee chaired by Dr. Nathaniel Berlin, the NCI Clinical Director, was appointed to review the experience at NIH in this area and suggest any needed changes. The committee met thirteen times, mostly with the Clinical Directors of each Institute. The Executive Secretary of the NACC Subcommittee on Diagnosis and Treatment, Dr. Margaret Edwards, reviewed the ethical standards of 21 professional societies and the committee provided information on their practices regarding ethics policies.
The committee suggested a number of changes, mostly to clarify and elaborate the existing definitions, policies and practices. For example, the definitions of classes of patients were enlarged and the details of informed consent were expanded. The use of group actions was clarified. A review of the Outpatient Department was recommended. As before, the Clinical Director of an Institute has the ultimate responsibility for patient care in that Institute. He is the senior physician in that Institute (“Ad Hoc Committee,” Dr. Berlin, Chairman, Ad Hoc Committee, to Members of the Ad Hoc Committee, September 9, 1965).
It is of interest that at about this same time this subject was looked at by Mr. Edward Rourke, Assistant General Counsel, Office of the PHS Surgeon General. In an astute memorandum dated October 26, 1965, to Surgeon General William Stewart, he pointed out that very little had been done anywhere to bring to bear on the subject attention from outside the medical and scientific research fields, including the law. He predicted that the public was very likely to want to have a greater say about how clinical investigations would be carried out. He stated:
The judgements that will in the long run have the significant impact on clinical research will be those of the courts, Congressmen, trustees, and other “lay” representatives of the public. What I feel is overdue is recognition by the medical scientist that he will not ultimately make the rules that will govern his work in this area and that he can at best hope that those who will make them will have an adequate understanding of his problems and of the values he serves with such dedication.
If this be so, the time has long since come to move out of the medical-scientific context with its preoccupation with morals and ethics, and at least for the scientist to share the problem and, if he be allowed, the responsibility for its solution with others. The risks of doing so are obvious, but to continue in an isolation that has been largely characteristic to date only postpones an inevitable accounting with, I think, greater risks to the total research effort.
I say “preoccupation” with morals and ethics partly in sympathy with the scientist who, when faced with a problem not subject to the scientific discipline, apparently can think of nowhere else to turn, and partly with impatience for the almost pathological urge to ignore or minimize the basic, operative mechanism of society that sets the standards for the conduct of all of us -- the law. The scientist may not like the judgements the law is likely to make, but he can hardly ignore them for long and flourish.
This brings me to my second point. The law to date is hardly as vague and uncertain as it is sometimes made to appear, if attention is paid to it at all. Certainly how far it will go in the future to provide a secure basis for clinical research is not clear, and at present it provides no such basis for manipulative research on children or the mentally incompetent. But it begins firmly with the competent patient’s or subject’s free right to control the use of his person whether the purpose be diagnostic, therapeutic, or research. Only the individual, with all his ignorance, superstitions and foibles, can make the important choice and, being fully informed as possible, he is free to make it for particular reasons or for no reasons at all. While I do not mean to exclude other considerations, the basic proposition is that the decision to be a subject of research is not one to be made by the physician or scientists but one to be made by the subject.
It is the failure to observe scrupulously this one principle that will cause lay or public outrage and lawsuits that may threaten the whole field of clinical research. And I suspect that it is the scientist’s awareness that this principle is not always observed that disturbs him deeply and sends him groping for moral and ethical guides. I also suggest that scrupulous observance of this principle will reduce the problem to where it might be left largely to the scientific community to measure, as only an expert can, whether the potential scientific gain is worth the risks the patient or subject knowingly is asked to take. Granted the principle may need refinement and that, even so, it may in application prevent certain research from being conducted. But in general the use of human beings for research without their informed consent is not likely in my judgement to be accepted by our law or other aspects of our “lay” society however important to society that research may be.
More sophisticated statements of such a principle and of “codes” of conduct are possible, and several are available. Although none are beyond some criticism, both from the legal and other points of view, they fairly represent a consensus appropriate for utilization. I thus suggest a major problem is not to develop another formulation. Instead, it seems to me the greater need for the PHS is to define to what extent it has responsibility in the application and enforcement of the principles that are generally accepted.
Rourke suggested that the Public Health Service make a broadly based effort to delineate the PHS responsibility expressly in the grant area so that harm that arises beyond the reach of this delineation can fairly be said, in any quarter, to be the responsibility of others -- those who will and should remain in control of the situation -- the investigators and their institutions. [These observations of Mr. Rourke showed great prescience as can be seen from later developments in gene cloning, gene therapy, gene modification, and other advances in molecular biology and biotechnology.] (“Clinical Research,” Edward J. Rourke, Assistant General Counsel, to Surgeon General, PHS, October 26, 1965.)
Heart Disease, Cancer, and Stroke Amendments of 1965
The Heart Disease, Cancer, and Stroke Amendments of 1965, Public Law 89-239, 89th Congress, was signed into law by President Lyndon Johnson on October 6, 1965. President Johnson had established a Commission on Heart Disease, Cancer, and Stroke on February 10, 1964 with Michael DeBakey as Chairman; Sidney Farber, Lee Clark, and Frank Horsfall constituted the Subcommittee on Cancer. The Commission recommended the creation of “a national network for patient care, research and teaching in heart disease, cancer, and stroke.” At the apex of the network, 20 cancer centers were to be established within 5 years; at the base, 200 diagnostic and therapeutic stations were to be established. Each center would be distributed geographically to serve about 10 million in population. The cost for cancer activities was estimated to be $2.98 billion over 5 years ($357 million the first year). In the 1950’s Lee Clark, with support by Sidney Farber and the NCI, established the American Association of Cancer Institutes. Dr. Clark visualized this group as eventually forming the base for the network recommended by the Commission. Farber and Clark and Mary Lasker wanted a network of cancer centers each like the existing comprehensive centers (Memorial Sloan-Kettering Cancer Institute, M.D. Anderson Hospital and Tumor Institute, Roswell Park Memorial Institute, and the National Cancer Institute). Ten other centers of less comprehensive scope, including Dr. Farber’s Children’s Cancer Research Foundation, were functioning. They wanted the centers to be independent from the medical schools and closely tied to NCI. They were thwarted in the first instance by the legislative process and in the second by the Administration. The contents of the Bill as finally signed by the President on October 6, 1965, bore little resemblance to the recommendations of the Commission. The concept was weakened, e.g., “complexes” became “programs”; “coordination” became “cooperation”; and the categorical emphasis was lessened. Cancer received only 8% of the money of the Regional Medical Program, the program at NIH established to administer the Heart Disease, Cancer, And Stroke effort. This proposed extension of medical care with government support failed. Mary Lasker was very disappointed (“A National Program to Conquer Heart Disease, Cancer and Stroke,” President’s Commission on Heart Disease, Cancer and Stroke, February 1965, pp. 105-128).
The November, 1965 NACC Meeting
At the NACC November meeting, members focused on a presentation given on the e Field Studies Area Program on November 15, 1965. Included in this review was the program of the Virology Research Resources Branch. Material was provided to members of the Council prior to the meeting (28 pages of the 82 pages of total text were for the VRRB Program, and all contracts for Field Studies were listed). This material described how the with the added appropriation for the Special Virus Leukemia Program, the viruses-cancer activities had moved into high gear, especially in the production, certification, distribution and use of supporting resources. Some of the highlights of the program’s activities included the following: over 300 serologically distinct viruses had been recovered from humans. in order to maintain this success, it was projected that homotypic diagnostic reagents were needed in larger quantities, including those for the simian viruses. There had also been increased production on avian tumor viruses, antigens, antisera, and control sera; 400 sera per month were being used to make a diagnostic survey of breeding colonies. Fluorescent antibody procedures had been refined and several population surveys were planned for the future. Dr. John Bader was producing sufficient amounts of Rous associated viruses (discovered by Dr. Harry Rubin) to distribute samples to other investigators. A tissue culture of myeloblasts had been established, and herpes-like virus particles had been seen on electron microscopy in the cultures. In the CCNSC Program, 12 additional characterized cell lines were established (these added to the American Type Culture Collection make a total of 37 certified cell lines). Standardization had been imposed on cell culture media and serum supplements; fetal calf serum for tissue culture media had also been standardized. Diploid cell lines were being distributed to requesting investigators. Improvements were continuing to be made in the design, fabrication and use of special high speed zonal ultra-centrifugation rotors, permitting greater purification of virus preparations for further studies on tumor-causing and other virus preparations (in other fields, better vaccines had already been produced by this new technology). Developmental research had been applied to produce new and improved laboratory animals, including the marmoset, bushbabies, and tree shrews; diseases and lack of knowledge of norms of physiology plagued the use of imported monkeys, but these problems were corrected to allow not only clean animals, but adequate supplies of newborns in captivity. A battery of diagnostic reagents for detecting latent mouse viruses had been applied to a surveillance program for mouse production colonies; a symposium and training courses on the use of the reagents were established. RIF-free chicken eggs (eggs free of resistance-inducing factor needed for virus assays) were sent out to investigators and breeders (170 dozen eggs sent). A mycoplasma screening service had been established and a problem with contamination of tissue culture cell lines had been corrected. Developmental research was being applied to determine optimal freezing and thawing parameters for cells and cell lines. A contract to produce germ-free hamsters had not been successful. A major effort was being made to establish a tissue procurement system that would overcome the difficulty of individuals to obtain human embryonic tissues and specimens from cancer patients, especially leukemia specimens. During 1965, about 730 sterile autopsies were performed; from these, 14,000 vials (1 gram of tissue per vial) were collected and 10,000 vials were delivered to 75 investigators. Of 500 requests for tissues, about 95% were met. Screening of known oncogenic viruses was being made in monkeys and baboons. Dr. Maurice Hilleman of Merck Sharp & Dohme had been a grantee for years; however, a ruling from the Surgeon General no longer allowed staff of commercial organizations to have grants. NCI quickly awarded a contract for Dr. Hilleman because of his outstanding research, especially on vaccines. He had demonstrated that Adenovirus Type 7 and SV40 viruses were oncogenic. He had also showed that protection against large doses of infectious oncogenic virus could be achieved by subsequent immunization with irradiated, killed tumor cells transformed by the same virus type. At this time the only method for determining the sizes of viruses was filtration through “gradacol” membranes. The VRRB extended their production from England with a small contract without which these membranes would not have been available. Also at this time virus preparations were beginning to be highly purified, and new physicochemical procedures, including use of the special ultracentrifugation rotors, were being refined as resources that could help determine the detailed structure of oncogenic viruses. Thus, the stage was set to determine which parts of the smaller oncogenic virus molecules were actually producing oncogenic changes in cells, which parts were necessary for replication of virus, and which parts were for other functions.
The total dollars for viruses-cancer studies in the Field Studies area for Fiscal Year 1965 was $6,028,300 and budgeted for Fiscal Year 1966 $7,511,700. As a result of reorganization, transferred two groups from the Intramural part of NCI to the Field Studies area: 1) the Viral Oncology Section (from the Laboratory of Viral Oncology) to become the Viral Leukemia & Lymphoma Branch (Dr. Rauscher); and 2) the Laboratory of Viral Carcinogenesis to become the Viral Biology Branch (Dr. Dalton). Dr. Stevenson’s VRRB would be designated the Viral Carcinogenesis Branch. With these changes, the total amount budgeted for viruses-cancer work in Field Studies would be about $11.5 million and would add 65 positions; $3.5 million was budgeted for the new special hazard building (“Field Studies Area Program Presentation to the National Advisory Cancer Council,” Program Review Book, November 15, 1965, pp. 55-78).
External Contract Research Centers
At the October 1965 NACC meeting there was a general discussion on the desirability of creating for biomedical research organizations similar to those sponsored by other Federal agencies (e.g., IDA. RAND Corporation, MIT Lincoln Laboratory, etc.) for the performance of evaluative, analytical, planning and other functions.
The Council asked NCI staff to prepare a brief statement on these organizations and some typical assignments might be given to such organizations. On November 1965 the Associate Director for Program sent to the NACC a ten-page document identifying 61 such center, an analysis of the types of activities performed, working agreements with sponsoring agencies, etc. Ten tasks were outlined to illustrate some of the assignments NCI might make if External Contract Research Center were in operation. Following discussion no clear recommendation was made (“External Contract Research Centers,” to the Members, National Advisory Cancer Council from the Associate Director for the Program, November 5, 1965).
Scientific Directorate Functions
On November 29, 1965, Dr. Endicott sent to members of the Scientific Directorate a detailed set of instructions for operations of the Directorate, including program and contract reviews. The NCI had completed its reorganization and had received approval from the Surgeon General. The reorganization effort extended over three years (see Scientific Directorate minutes for August 21 and September 4, 1962; April 2, June 28, July 2, and July 15, 1963; June 30 and July 14, 1964; and March 9, October 5, and October 19, 1965; these informative documents reveal recurring problems, a variety of proposals, and absence of clear consensus on the best manner in which the Directorate is to conduct its evaluative role). Dr. Endicott’s November 29 memorandum listed six roles for the Scientific Directorate:
1. Broad policy development and formulation.
2. Evaluation of programs and program plans.
3. Coordination of programs.
4. Resolution of differences between a Scientific Director and a Program Review Committee or a Contract Review Committee.
5. Primary review of contracts of critical program significance for which review by established committees would be inappropriate.
6. Review of proposals for promotion of senior professional staff.
The memorandum goes on:
Evaluation of programs and program plans (item 2.) has repeatedly engaged the attention of the Directorate. The major decisions are decisions on programs (i.e., in comparison with decisions on individual contracts) since these decisions broadly determine whole series of far-reaching subsequent actions and additional decision-making frameworks. For example, such program decisions should be made prior to the invitation of new project proposals (contracts or grants). Moreover, major program decisions need to be made within the full perspective of the total NCI program if the appropriated funds and other resources are to be most effectively allocated and used for cancer research. Because the NCI is a public agency, our reviews of programs (including contracts) must not only be sound, but visible, and soundly documented. Recent actions of Congressional committees (Senate Appropriations Committee Report on the 1966 Supplemental Appropriation, pages 32-33; see also the Conference Report, pages 7-8), and of the National Advisory Cancer Council (minutes of the August 1965 meeting), emphasize this need for the Scientific Directorate to review all NCI programs within the overall Institute perspective.
The Directorate must assure itself that individual contracts are reviewed well for intrinsic merit. But, as it has agreed in the past, this does not mean that it must review each contract proposal individually. Once a system of satisfactory program review has been developed, the Directorate may feel it can depend primarily upon program quality to reflect, in summation, the quality of an area’s contract reviews. It does have the responsibility for assuring the Director that contract proposals are receiving sound review. (See below, CONTRACT REVIEWS.)
PROGRAM REVIEWS
The outline below of review of program plans for the four newly organized major program operating areas (General Laboratories and Clinics; Extramural Activities; Etiology; and Chemotherapy) is based on recent discussions of the Directorate. Each program leader will annually present a description of his program and program plans. Major objectives of the area, program logic with consideration of optional approaches, and program plans extending beyond the following year will be presented, but emphases, selection of detailed items for discussion, and the format of presentation may vary with the program area.
Programs of the Etiology and Chemotherapy areas will be described in broad strokes, showing program philosophy, logic, objectives and relationships. Charts showing integration of program elements will be used as appropriate. Emphasis will be given to contract-supported efforts. The presentation should include plans for shifts in contractual activities when needed, to bring ongoing efforts into line with program objectives and plans. Summaries and progress statements of individual contracts (see below) should be included. From time to time program leaders may bring before the Directorate general and specific problems concerning contracts or, with respect to internal operations, plans for major changes involving space, positions, dollars, and other resource needs. Efforts that may have substantial impact on other program areas will be specifically identified.
In the area of General Laboratories and Clinics the Scientific Director will present a program review with the following elements: (1) broad philosophy, hopes, aspirations and objectives; (2) program plans of major scope and direction with an indication of changes contemplated involving substantial space, dollar and other resource needs and contract demands; (3) work undertaken that will have a substantial impact on other program areas, particularly when it involves contracts; and (4) issues on which he would like advice from the directorate.
In the Extramural Activities area the Associate Director will present, in very broad strokes, objectives in the grants area with some assessment of the scientific content, deficiencies and plans for new areas in which the grants staff will make special efforts. Emphasis will be on: (1) selected information he judges to be valuable for the Directorate, including periodic assessment of a system of contracts and grants review; (2) cross-impacts upon other areas, e.g., programmed grants in chemotherapy, centers grants, single instrument support, etc.; and (3) items on which he would like advice from the Directorate.
The primary benefits of program reviews result from the program leaders and their staffs pulling together in an integrated manner the various activities within the program, juxtaposed against program objectives in such a way that priorities can be more easily established by them. The requirement for written statements, which are necessary as part of the annual review for the Council and for other purposes, further aids in sharpening up program activities. Such written material should also form the basis for required NIH annual reports and for budget development. In these presentations special efforts must be made continually to include plans on a longer-range basis (in the perspective of at least three years). With such reviews and documentation the Scientific Directorate will be in a better position to carry out its role of evaluation of programs and program plans.
The next sections of the memorandum set forth detailed requirements for CONTRACT REVIEWS and INFORMATION FOR NACC (based on motions of the Council at its recent meeting). The final part of the memorandum is:
IMPLEMENTATION OF THESE POLICIES
All NCI staff are responsible for carrying out the duties indicated for them in this memorandum; the focal point for implementation, however, is the Associate Director for Extramural Activities. He will issue the required detailed procedures in writing and establish the new contract review committees (Etiology Contract Review Committee; Drug Development Contract Review Committee; Drug Evaluation Contract Review Committee; Endocrine Contract Review Committee).
The various Scientific Directors should now send their nominations for membership on the appropriate contract review committees and program review committees for the Etiology and Chemotherapy areas to me through the Associate Director for Extramural Activities.
The Personnel Officer will prepare the necessary instructions for implementing the promotion reviews (see minutes of the Directorate, October 19, 1965. Promotion reviews will be conducted by the Core Members of the Scientific Directorate (see attached membership list of the Directorate).
I look forward to having this new system in full operation by the end of this calendar year.
The attachment to the memorandum:
Membership of the NCI
Scientific Directorate
Members (Voting):
Core Members:
C. Gordon Zubrod, Chairman
Paul Kotin, Vice-Chairman
Carl G. Baker, Executive Secretary
Nathaniel I. Berlin
Robert E. Learmouth
Eugene J. Van Scott
T. Philip Waalkes
Other Members:
W. Ray Bryan
William M. Haenszel
Samuel S. Herman
Seymour Perry
David P. Rall
Saul A. Schepartz
Margaret H. Sloan
Associate Members (Non-Voting):
George A. Brandner
James F. Kieley
Deputy Scientific Directors may substitute for Core Members when absent (no other substitutions).
Attendance by others will be by invitation only (“Scientific Directorate Functions (including Program and Contract Reviews,” to the Members of the Scientific Directorate, National Cancer Institute from the Director, National Cancer Institute, November 29, 1965).
1966
Completion of the NCI Reorganization
In a memorandum dated February 1, 1966, Dr. Endicott announced the approval of the Surgeon General of the NCI reorganization. The main changes in addition to those listed above were: Dr. Eugene Van Scott would become Scientific Director for General Laboratories and Clinics; and Dr. T. Philip Waalkes would become Associate Director for Extramural Activities. Dr. Samuel S. Herman would be the Deputy Associate Director for Extramural Activities and there would be four Branches: Special Programs Branch (Dr. William A. Walter); Awards Review and Technical Administration Branch (Open); Cancer Therapy Evaluation Branch (Dr. Margaret H. Sloan); and Grants and Research Contracts Branch (George A. Brandner). As indicated above transferred from the Intramural Area were: Dr. Ray Bryan and two Branch Chiefs and their staffs (Dr. Dalton and Dr. Rauscher). Dr. Stevenson’s VRRB became the Viral Carcinogenesis Branch.
Meeting on February 5-6, 1966 of the NACC Subcommittee on Heart Disease, Cancer and Stroke
On February 5, 1966 the Council Policy Subcommittee on Heart Disease, Cancer and Stroke (Drs. Sidney Farber, Chairman; Philip Cohen; Roger Egeberg; and Ruben Flocks) met with members of the Association of Cancer Institute Directors for discussion of the Heart Disease, Cancer and Stroke regional program developments. This joint meeting, followed by a day’s meeting of the Subcommittee itself, would bring the participants up to date on activities in the Heart Disease, Cancer and Stroke area and enable the Subcommittee to discuss implications for the NCI programs for the purpose of informing the Council at the March, 1966 meeting. The agenda for the February 6 NACC meeting included:
1) Report of trips to research organizations......Dr. Endicott
2) Review of Heart Disease, Cancer and Stroke.....Dr. Farber
3) Discussion of ACID meeting.
4) Implications of Heart Disease, Cancer and Stroke Activities for NCI programs.
a) clinical training grants.
b) clinical research center grants.
c) radiation therapy.
d) chemotherapy.
e) cancer detection.
f) support of cancer institutes.
The first issues discussed at the meeting was the reduction of NCI funds and the cutback of Collaborative Research monies as a result of the Wooldridge Committee recommendation. The amounts awarded for recommended competing continuation grants would be held to no more than the current amounts plus 5% increase. The Heart Disease, Cancer and Stroke Bill would possibly be a factor in reducing the funds made available to NCI.
Dr. Farber again raised the issue of the relationship between the NACC and the NCI staff, emphasizing the need to make it clear that the Council and staff work together in common toward the same goals. He stated that the staff should feel that Council meetings are useful and that the Council members must feel that they are useful. He thought the Council should not be only an advisory group. The paper work prepared by NCI for the Council should be done only for a purpose and in less volume. (The large volume of paper work prepared by NCI had been in response to the Council’s requests for more information).
Dr. Endicott reported on his visits to various organizations around the country and listed the places where programs in cancer could be developed if NCI received an increase in appropriated funds. These places included: University of Washington; University of Minnesota; a grouping of cancer organizations in the Detroit area; University of Iowa; at Houston at the M.D. Anderson Hospital and Tumor Institute and the Baylor College of Medicine; Tulane University; the University of Southern California; University of Pennsylvania; and Johns Hopkins University. San Francisco, he indicated, might be ready in two years. LSU had no interest. Dr. Farber thought Dr. Endicott gave a good recital of current possibilities. In Dr. Meader’s visits around the country he found interest in cell biology in only one instance (Dr. Saul Kit at Baylor).
NCI already had received 40 applications for training grants totaling about $5 million, though only $3.4 million was available in the budget. It was expected that about an additional 100 training grant applications would be received in the fiscal year (totaling about $5-6 million). In training grants in radiotherapy, additional equipment would be needed. Funds from the Heart Disease, Cancer and Stroke program should result in more support for additional service and educational programs in institutes, and NCI could come along behind them with research planning dollars followed by research dollars. There could be fluid institutional and regional funds within the regional framework of the new program (the Regional Medical Program). It was not clear in early 1966 how the Program would develop.