Biologics Regulation and ResearchThe People and Work of Buildings 29 & 29A

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Buildings 29 and 29A are nationally significant to the history of medicine and public health because within their laboratories National Institutes of Health (NIH) and then the Food and Drug Administration (FDA) staff helped to conquer some of the deadliest infectious diseases. In their regulatory role, they had the national responsibility to license the NIH and FDA staff in these buildings tested and licensed vaccines, antitoxins, blood products, and other biologics to ensure their safety and effectiveness. To support this mission, they did performed their own scientific research which resulted in the development of important to develop important industry standards and even new vaccines. Some of the most well-known scientists of the 20th century worked in these buildings, as well as key administrators and others who supported their work and the mission of biologics regulation. The biographies Biographies section profiles 22 of them. This online exhibition also shares information about the research, regulations, and work conducted in these two laboratory buildings between 1960 and 2014. A variety of diseases, vaccines, and other biologics are discussed, with links to articles and other websites for further research. While the buildings are no longer in use, the legacy of their exemplary staff and their important work endures.

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Bronze plaque installed in the entryway of Building 29.

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Dave Derenick

The Office of NIH History & and Stetten Museum preserves and interprets the material culture of the scientific work of the NIH. The museum Stetten Museum is hosting this online exhibit about Buildings 29 and 29A and the biologics research and regulation conducted there to inform the public of the breadth and significance of biologics research and regulation performed in the two buildingsBuildings 29 and 29A. The NIH Stetten Museum worked closely with the NIH Office of Research Facilities and the Food and Drug Administration ( FDA ) History Office to document the two buildings for posterity.

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The Biologics Control Act, or the Virus Toxin Act, was passed in 1902 after In 1901, 13 children died the previous year in St. Louis, Missouri, from diphtheria antitoxin which had been contaminated by tetanus. An investigation discovered that one of the horses used in the manufacture of the antitoxin had live tetanus organisms in its blood and was the source of the infection. DrDr. Joseph J. Kinyoun of the Marine Hospital Service’s Hygienic Laboratory (the ancestor of the Division of Biologics Standards [DBS] and the NIH more broadly) had long recognized the danger posed by the availability of unstandardized and poorly tested diphtheria antitoxins. Kinyoun wanted to establish an independent antitoxins and had pushed for an independent (not commercial) testing laboratory; this incident to gave Congress the impetus to act.

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Newspaper clipping from St. Louis Republic on November 2, 1901 with photo of the alleged horse used for diphtheria antitoxin.

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FDA History Office

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Congress then introduced enacted two bills , both enacted on July 1, 1902. One bill broadened the Marine Hospital Service's mandate by re-establishing it as the Public Health and Marine Hospital Service. The other bill authorized this new service Service had previously focused on the health of sailors; now it could focus on broader issues. The second bill authorized the Service to regulate the sale and transportation of any virus, therapeutic serum, toxin, or analogous product in interstate commerce or from a foreign country. All establishments engaged in the sale, barter, or exchange, or offering for sale, barter, or exchange of biological products in interstate commerce had to be licensed, and eventually each product had to be licensed as well. Each licensee had to be inspected annually by agents and officers of the Federal government. The second This Congressional act is known as the Biologics Control Act or the Virus-Toxin Act. This The act has been amended by Congress several times to incorporate additional product classes, including blood, blood components, and blood derivatives. Today the regulated biologics include vaccines, blood and blood products, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.

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An image of the 1902 Biologics Control Act or the Virus Toxin Act.

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The Division of Biologics Standards [Public Health Service Publication No. 1744] by Dr. Roderick Murray published in 1968.

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In 1962, the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act of 1938 were passed after thalidomide, a sleeping pill used widely in Europe, was found to cause birth defects. Thalidomide had not been marketed in the U.S. thanks to the FDA, but it had been used in a pharmaceutical company’s investigational trial and 624 of the 20,000 American participants were pregnant women. There were 17 documented cases of birth defects caused by thalidomide in the USU.S. The 1962 amendments strengthened the regulations for drug safety and for testing drugs in clinical trials. They also required manufacturers to provide “substantial evidence” that their drugs were effective for their intended use and that the drugs had to be produced using “good manufacturing practices,” which required inspections of manufacturers every two years and yearly registration. The 1962 amendments also applied to blood banks.

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Division of Biologics Standards

In 1955, the The Division of Biologics Standards (DBS) was formed as an independent entity at the NIH, but as the continuation of a biologics regulatory function that had at NIH since 1902. The predecessor of the DBS was known as Control was established in 1937 at NIH from the laboratory that had responsibility for biologics. In 1944, the division became the Laboratory of Biologics Control, formed in 1944 from . And in 1955, the Division of Biologics Control, which had been established in 1937. Its staff was spread out amongst multiple buildings on the NIH campusStandards (DBS) was formed as an independent entity at the NIH, but as the continuation of the previous division and laboratories. The DBS was responsible for establishing and maintaining standards of quality and safety of all biological products. The safety, purity, and potency of all biologics must had to be established before the product was licensed by DBS.

The DBS was formed in the wake of the “Cutter Incident.” In 1955, the year following a field trial that showed the Salk inactivated (killed) polio vaccine to be safe and effective, the DBS licensed several firms to produce the vaccine. One firm, Cutter Laboratories, accidentally released vaccine that retained live polio virus, resulting in 260 paralytic cases of the disease in children, a disaster that caused panic among parents and scientists alike. The vaccine from Cutter Laboratories was pulled from the market on April 27, 1955, but the damage had already been done. The Cutter Incident became a defining moment in the history of vaccine manufacture and government oversight of vaccines. It occurred because the rigorous safety precautions currently used in the field trials were not required , at the time , for the production of commercially-produced licensed vaccines. The government realized it needed to strengthen its role in biologics regulation. The Cutter Incident led directly to the transfer of the regulation of biologics from the Laboratory of Biologic Controls to the DBS.

DBS staff was spread out among multiple buildings on the NIH campus. In 1960, Building 29 opened, providing a consolidated space where the DBS staff of DBS could work together. The 1950s 1960s through the 1970s were exciting and busy times for biologics regulation. As vaccine research flourished, new scientific advances in tissue culture were made and important changes were made for regulating blood and blood products. This necessitated the construction of Building 29A in 1967, to provide an annex of for DBS laboratory space for the DBS staff.

Transfer to FDA and Biological Products Review

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The legislative history leading to the codification of the 1902 Biologics Control Act into the 1944 Public Health Service Act included a proposal that biological products have to be ‘efficaciousness’, in addition to the safety, potency, and purity requirements already in the statute. However, the proposed additional requirement of efficaciousness was not carried into the 1944 Act. In March 1972, the Government Accounting (later called Accountability) Office (GAO) reported that DBS had not required effectiveness of biological products despite the fact that they were also ‘drugs’ under the statutory definition, and drugs had to be effective as well as safe under the 1962 Amendments to the Food, Drug, and Cosmetic Act. In the same month, NIH announced its intention to review all of its biological products and issued a call for substantial evidence of effectiveness, the standard that was applied to drugs. During a May 1972 Congressional hearing, Department of Health, Education, and Welfare (DHEW) Secretary , Elliott Richardson , announced that DBS should be transferred to FDA, which was carried out the following month.

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A GAO Government Accounting Office report released in March 1972 called out DBS for allowing hypopotent vaccines to remain on the market (from the Pensacola News Journal on Friday March 31, 1972).

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FDA History Office

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When the NIH Division of Biologics Standards The NIH DBS staff of nearly 270, including more than 100 scientists and health professionals, were transferred officially to the FDA on July 1, 1972, and became the Bureau of Biologics, known as "the Bureau." The core work of the Bureau's biologics regulation and research remained the same: licensing both manufacturers and their products, ; creating the physical and written standards and carrying out the necessary research to apply them to biological products, ; inspecting manufacturing facilities to confirm compliance with standards, ; testing product samples prior to their commercial distribution, ; and monitoring experiments involving new biological materials (investigational new drugs).

In February 1973, FDA finalized plans to conduct a systematic efficacy review of all licensed biological products, modeled on its review of over-the-counter drug products that had been launched the previous year. Commissioner Charles Edwards appointed six advisory panels of experts that would review the evidence and assign each biological product to one of the following categories: safe and effective; unsafe and/or ineffective; requiring further study but to remain available in the interim; and lacking sufficient data to be determined safe and effective and recommended for market removal. Much as the case with new drugs, the proof of effectiveness would be expected to derive from adequate and well-controlled investigations. And much like the case with drugs, the review lasted decades. Along the way, though, some licenses have been revoked, such as in 1977 when FDA announced its intention to revoke the licenses of eight skin tests for tuberculosis, diphtheria, and other diseases and conditions.with drugs, the review lasted decades.

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The month following the DBS transfer, FDA announced a comprehensive external review of biologics for efficacy (from The Independent (Long Beach, California, August 18, 1972).

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FDA History Office

The retrospective biologics review also included an evaluation of product labeling, and in one quarter of 1973 alone the Bureau received nearly 500 submissions of proposed labeling from manufacturers of both licensed commodities and products awaiting licensure. Advertising, too, was part of the Bureau’s oversight, that function first assigned to FDA for prescription products under the 1962 Drug Amendments. For example, in 1973, Bureau monitoring of professional journal advertising resulted in a notice to one manufacturer for corrective changes to claims made.

The biologics review panels had completed their reviews or issued their final reports in 1980. For For example, the Panel on Review of Bacterial Vaccines and Bacterial Antigens (with no U.S. Standards of Potency) deemed none of the products they reviewed safe and effective. On the other hand, the Panel on Review of Blood and Blood Derivatives determined that most blood bank and plasma fractionation products were safe and effective. Implementing their Implementing the panels' recommendations, as FDA learned through its retrospective reviews of prescription drugs, would take longer. However, as mentioned previouslyin 1977, a number of tests that the Panel on Review of Skin Test Antigens deemed either unsafe or ineffective, misbranded, or inconclusive with potential risks outweighing benefits were removed from the market.

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The FDA Center for Biologics Evaluation and Research (CBER) is the home of biologics regulation today. When DBS was administratively transferred from the NIH to the FDA, it was called the Bureau of Biologics. During the 1980s and 1990s there was significant organizational change in biologics at the FDA. In 1982, the Bureau of Biologics merged with the Bureau of Drugs to form the National Center for Drugs and Biologics (NCDB). In 1983, the biologics component was renamed the Office of Biologics Research and Review (OBRR) within the Center for Drugs and Biologics (CDB). In 1987, more changes happened when the CDB separated into two centers: the Center for Biologics Evaluation and Research (CBER), which was formerly the OBRR, and the Center for Drug Evaluation and Research (CDER). CBER has remained the name for the biologics regulation team at the FDA ever since. In 2002, some functions of CBER were transferred to CDER, to allow CBER to focus on regulating vaccines, gene therapy, tissue transplantation, and blood safety. FDA’s review of new pharmaceutical products, which had been partially done by both CBER and CDER in the past, would be was consolidated to into CDER.

Architectural Documentation before Demolition

This online exhibition about Buildings 29 and 29A and the research conducted there is part of the process to mitigate the adverse effects of the planned demolition of the buildings.

The FDA Center for Biologics Evaluation and Research (CBER) moved from the NIH to the FDA White Oak Campus in 2014. This move completely vacated Buildings 29, 29A, and the circa-1994 Building 29B. Building 29B has been reoccupied by NIH staff, following moderate renovation. NIH completed feasibility studies and determined in 2020 that it is not viable to reuse Buildings 29 and 29A, and demolition is planned. As these are historic buildings on Federal property, Section 106 of the National Historic Preservation Act (NHPA) and its implementing regulations (36 CFR §800) must be followed. As part of the Section 106 process, consultation with various parties, including local government, historical societies, and the public took place before a Memorandum of Agreement (MOA) was entered into between the NIH and the State Historic Preservation Office , of the Maryland Historical Trust (MHT), since demolition of buildings is an adverse effect to historic properties. This online exhibition and the Historic American Buildings Survey (HABS) architectural documentation of Buildings 29 and 29A presented here (survey and fieldwork were completed July 12–14, 2021) is part of this effort. While Buildings 29 and 29A are no longer in use, the legacy of their exemplary staff and their important work endures.

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Biologics Regulation and ResearchThe People and Work of Buildings 29 & 29A

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Division of Biologics Standards

Transfer to FDA and Biological Products Review

Architectural Documentation before Demolition

Office of NIH History and Stetten Museum