tinued to license vaccines produced in the animal cell cultures known to be subject to contamination. POTENTIAL ADVANTAGES The potential advantages of growing virus vaccines in a secondary or serially propagated cell population, such as I have just described, are embodied in two words: "safety" and "standardization." Serially cultured normal cells such as those developed by us from human tissue some 10 years ago have the following advantages over primary cell cultures: 1. These cells can be frozen in liquid nitrogen freezers for apparently unlimited periods of time, reconstituted at will and exhaustively tested by dozens of laboratories prior to their use as vaccine virus substrates. This cannot be done with primary cells. 2. Enough vaccine can be produced from the cells of a single tissue derived from a single donor to immunize hundreds of millions of people. This is the ultimate in cell standardization and cannot be realized with primary cell cultures, each of which comes from a different animal with different characteristics. 3. Unlike monkey cells, the human diploid cell strain WI-38 tested in hundreds of laboratories throughout the world has never been found to contain an indigenous contaminating micro-organism. 4. The same exhaustively tested cell population can be used by several different vaccine manufacturers unlike the thousands of unstandardized primary cell populations now required. 5. A significant diminution in the annual slaughter of monkeys. for their kidneys used in polio vaccine manufacture can be effected. Some of these species are threatened with extinction and their handling has killed 25 workers worldwide from at least two exotic virus. diseases. WI-38 The primary cell populations in current use for vaccine production in this country are derived from dog, chicken, duck, rabbit, and monkey tissues. Since DBS requires that the cultures derived from these animals be primary cultures, you can see why it is necessary to kill tens of thousands of these animals annually to provide a variety of cell substrates for virus vaccine manufacture. In 1961, we reported that serially cultivated human cells derived from the lungs of an aborted fetus remained absolutely normal in all respects for a period of 50 serial subcultivations and then these cells died. We also showed that these cells could be frozen in liquid nitrogen and stored indefinitely. Finally, we showed that these normal human diploid cells, as they are called, were absolutely "clean" in the sense that no contaminating foreign viruses or micro-organisms could be found in them. As a result of our confidence in one strain of these cells called WI-38 and their clear superiority to existing primary monkey kidney cell substrates, we produced a polio virus vaccine in them and proved the efficacy of this vaccine in man in 1962. POLIO VACCINES From the time that polio vaccines were first licensed in this country by DBS in the late 1950's and until last month, such vaccines were grown in primary cultures of monkey kidney cells. Each monkey is a universe unto itself and may carry harmful viruses in its cells, unlike WI-38. Therefore, the thousands of different kidneys going into polio vaccine production provides the ultimate in an unstandardized heterogenous tissue medium. The scope of this problem can be appreciated if one realizes that each lot of vaccine may require the sacrifice of several hundred monkeys whose kidneys are a veritable storehouse for the most dangerous kinds of contaminating viruses. In fact, monkey kidney is in this sense the "dirtiest" organ known. SV 40 In 1961, a virus indigenous to monkey kidney cells and known as SV 40 was found as a live contaminant in the Salk polio vaccine and an adenovirus vaccine administered to over a million people in the country. This virus, SV 40, produces tumors in rodents and can convert cultured normal human cells to cells with cancerlike properties. Despite this discovery in 1961, and despite what several scientists believe to be inadequate tests sanctioned by DBS to detect this agent, monkey kidney has been continued for 10 years to be used for the production of polio vaccine. Perhaps the risk of continuing to license vaccines produced in monkey cells would have been worth taking if no other substrate was available for the production of polio virus vaccine. But as indicated previously, the observation that normal human cells like WI-38 were a reasonable alternative was made in 1961-62. Yet, for reasons best known to DBS, they dug in their heels and for the next decade refused to offer any encouragement for the use of these cells in this country until foreign countries began switching over to the use of WI-38. This intractable position was maintained even though the military in this country-which does not come under DBS authority-sanctioned the use of a very effective adenovirus-a cold-like disease-vaccine for use since 1966. Adenovirus vaccines were, prior to 1966, made in monkey kidney cells, but for reasons already cited, the military made the change from monkey kidney cells to normal human WI-38 cells a full 6 years before DBS. ADENOVIRUS VACCINE As further evidence of the pace with which DBS reacts, the adenovirus vaccine used successfully in the military since 1966 was submitted to DBS for licensing for civilian use about that time and to this day a license has not been forthcoming. In the intervening years, the manufacturer has been asked to comply with a series of additional requirements that apparently the military has not seen fit to demand. In addition to SV 40, primary monkey kidney cells are known to harbor at least 20 other kinds of contaminating viruses. Vaccines produced in the human diploid cell strain WI-38, have been licensed by several countries since 1967. Yugoslavia was the first, followed by France, the United Kingdom, and the U.S.S.R. The American military has, as indicated previously, successfully administered a WI-38 grown adenovirus vaccine to nearly 1 million recruits. Even today, other types of adenovirus vaccines prepared in WI-38 are under development by the military. Why has DBS resisted encouraging the development of vaccines produced in normal human cells of proven success overseas and in the U.S. military while steadfastly defending continued use of primary monkey kidney cells with all of its inherent risk? DBS has never officially responded to this question-a common posture that I will consider shortly. In March of 1972, the first polio virus vaccine produced in normal human cells was licensed to Pfizer Ltd. by DBS for sale in this country, a full 10 years after the discovery of SV 40 contamination of primary monkey kidney cells and a full decade after the discovery of an alternative cell substrate. Not knowing what DBS's official view was during that decade, many observers felt that DBS has, in respect to primary monkey kidney versus WI-38, adopted the philosophy that it is better to live with the real devil you know rather than an hypothetical devil you do not know. As indicated at the outset, this situation is one of several that speaks to the point concerning the slothful reaction by DBS to advances made in the field of vaccine development. RUBELLA VACCINE In 1961, the first rubella-German measles vaccine was licensed by DBS. At least four groups of eminent scientists had developed strains of attenuated rubella viruses, each of which was a candidate strain for the first vaccine to be licensed. In 1969, DBS awarded the first rubella vaccine license to the firm that ceased to work on its own strain and chose that developed by DBS scientists. An alternative explanation, given by the manufacturer in question, is that the "Benoit level B-the commercial strain— and HPV-77 duck viruses-the DBS strain-were considered acceptable for large-scale work in children. The HPV-77 strain was chosen as the prime candidate for further vaccine pursuit by our laboratories in the best national interest of concentrating on a single virus which could be brought to general use in the shortest period of time." Under the circumstances, DBS could have hardly been expected to behave otherwise. During the preceding years, when DBS scientists were developing their rubella strain, considerable national and international publicity for DBS's strain was generated by its public relations staff. It now appears that the DBS rubella strain produces more undesirable side effects in recipients than do the remaining two strains, and it is very likely that in the next few years we will see a shift in use from the DBS rubella strain to one of the earlier unsuccessful candidates. WI-38 SUBSTRATES A reenactment of this scenario is now under way in which some of the players are changed but will act in a familiar plot. DBS will be faced within a few years of choosing to license some human virus vaccine produced on a substrate developed under contract to them at a cost so far of $1 million-or a similar vaccine produced on a substrate developed by others—say, WI-38. If that decision will be made by the DBS staff or by persons handpicked by them, then there is little doubt how that decision will go. DBS IMAGE My final point concerns a host of criticisms that have been leveled at DBS by many eminent scientists, for the most part bearing on its image as an agency that rarely acts but only reacts. Instead of assuming a leadership role in the area of biological products control, in the view of many DBS has assumed a role subservient to its constituency. This ultraconservative subservient to its stituency. This ultraconservative position by DBS is best illustrated by the degree and kind of risk taking in which it has been involved. In general the greatest advancements made in human virus vaccine development in the past 20 years have been made by American medical scientists funded with public funds. Yet, these advancements when they have yielded new vaccine virus strains or new manufacturing processes have had their major tests for safety and efficacy in other countries. It seems to have happened by chance or otherwise that the major risks are undertaken in other countries. The live polio vaccine was licensed by DBS only after 15 million people were fed vaccines in the Soviet Union. The live measles vaccine received its first major test in Upper Volta. There are other examples. The DBS has acted in many major areas by simply not acting at all, thus fomenting controversy and exacerbating differences that could have been aired and easily resolved. The tragedy is that the avoidance of major decisions by the DBS is unjustifiable for a regulatory agency for it inevitably works to the disadvantage of the public it is charged to protect. RECOMMENDATIONS On the basis of the aforementioned position, I would like to suggest the following recommendations for your consideration: 1. That all national biomedical control activities be placed under a single director and within a single agency. That is, the activities of the FDA, DBS, and the comparable control activities of the Department of Agriculture and the CDC be combined in an independent Consumer Safety Agency. Many of the activities of these agencies and others now overlap, and because they require equivalent kinds of expertise and laboratory facilities they represent a wasteful dissipation of effort. Furthermore, the distinction between those products that should be controlled by the FDA and those controlled by the DBS are becoming less discernible. The grey areas could be covered simply and more efficiently by an amalgamation of not only these two agencies but all Federal agencies responsible for the public health. Such an amalgamation of agencies should result in a cross-fertilization, where some control activity now unique to one agency could be changed or adapted so as to improve a similar activity in another agency. 2. The new agency should depend more on the judgment of expert panels with rotating memberships for scientific decisions and less on in-house personnel. These panels would be formed along the lines of existing study sections that advise the NIH on research grant applications and which have resulted in the highly successful and highly respected peer review system. The decisions of these proposed panels which would judge product safety, potency, purity, and efficiency would be in the form of recommendations to the director and his staff. One or more of these panels should oversee the research activities of control authority personnel. 3. No control authority should be permitted to sit in judgment of products or product components when the choice is between substances developed by that control authority and those competing with it from other laboratories. This result can be effected in either of two ways: (a) Limit research activity by control authority scientists to those areas directly related to the control and measurement of product safety, purity, potency and efficacy; or (b) disallow any control personnel from engaging in decisionmaking when a product or product component developed by them is competing with similar materials developed by others and for which licensing approval is requested. This is best accomplished by the system of expert panels drawn from the national biomedical community described in "2" above. 4. Establish within the DBS or its counterpart agency a Director or Deputy Director of Research to oversee the limited research activities appropriate to the agency's mission. However, if research at DBS is to continue to have the essentially undirected and subordinate role it now has, then the many competent scientists now there should be allowed to move on to an environment where they will enjoy a full flowering of their capabilities. 5. Replace the current DBS leadership with new individuals recruited from the biomedical community other than from the DBS itself. The scientific activity and personnel policies and responsibility of the DBS which have come under fire in recent months have so polarized its personnel and lowered morale that to choose a successor from within DBS ranks would be, in my judgment, a serious mistake. A search committee for a new Director of the DBS has in fact just been formed. This leadership change should also include reorganization by amalgamation of DBS responsibility with those of the FDA and other agencies responsible for the public health. This should include appointment of a scientific Director and establishment of an active system of expert advisory panels in all areas in which major decisions on the control and licensing of biological products depends upon the expertise of several scientists. UNEVEN POWER STRUCTURE OF DBS At present the structure of the DBS is uneven. Almost all of the power is centered in the Director with too little delegation of power, responsibility, and authority to others within the organization. A strong active middle echelon of administrators and scientists with authority to make decisions at a variety of levels is lacking. There is no limit to the Director's term of office, which is an unsatisfactory arrangement in any institution. His decisions are apparently unappealable and not subject to peer review or even effective peer support. This re |