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

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In addition to these moves in the regulation of blood, the Bureau quickly proposed revisions to the licensing standards for blood plasma, the source for various products including gamma globulins, antihemophilic factor, and serum albumin. Also, as mentioned earlier, previously only about 500 interstate blood banks were regulated by the federal government; the 6000-7000 intrastate blood banks operated with little to no oversight. The Bureau invoked authorities under the 1938 Food, Drug, and Cosmetic Act to apply to all blood collection and processing centers. Blood banks and other blood collection facilities now had to be registered and inspected. Plasmapheresis centers (sites where blood is collected, the plasma is separated from the red blood cells, the latter are returned to the patient, and the plasma either treated and returned or repurposed) had to be licensed and inspected. Nearly 6000 establishments were registered in the first 15 months, and Bureau and Bureau-trained field office personnel inspected about 1000. The Bureau trained FDA field investigators such that the latter were able to take over the inspection responsibilities of the nearly 250 plasmapheresis facilities by 1977. Two years earlier FDA for the first time revoked a biologics establishment license for cause, a recidivist plasmapheresis firm. In 1977 FDA pursued its first criminal prosecution of a plasmapheresis firm. In this case, the corporation was charged with providing false documents to FDA, intentional and non-intentional violations of the Food, Drug, and Cosmetic Act by adulterating and misbranding plasma, and violation of the Public Health Service Act by misbranding a biological product. A jury found the three charged officers of the firm guilty. Each was sentenced to 18-24 months in prison and their company fined $27,000. The plasmapheresis center and its ancillary facilities were enjoined and closed.add two images of inspector

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A significant change in oversight of blood came with the finalization of new good manufacturing practices for all blood banks, transfusion centers, and blood processing entities.  Among other provisions, these required testing all donations for hepatitis, standards were established for tests given to patients prior to the administration of blood or a blood product, any fatality involving a blood donation or administration had to be reported to FDA immediately and required recordkeeping for blood products was extended. A retrospective analysis of plasma derivatives submitted since 1960 up to 1973 indicated that almost all lots of plasma protein fractions had the Hepatitis B Antigen.

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Despite the 1988 voluntary agreement agency inspections of ARC facilities across the nation continued to present compliance failures, followed by formal regulatory notices and initiation of proceedings to revoke establishment licenses. In May 1993 ARC agreed to a consent decree, enforceable by court order, that stipulated a comprehensive series of changes to ensure the safety of the nation’s blood supply and the integrity of ARC’s blood program. Among the changes:  establishing a clear line of managerial control over quality control in all regions;  establishing a comprehensive quality control program;  enhancement of a training program to be required—along with an annual competency review—for all staff engage in blood programs, improvement of its computer system, records management, and its policies for following up on reporting errors, accidents, and adverse events; and annual performance audits of each of its 47 blood program regions.add image of red cross newspaper clip

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The Center for Biologics Evaluation and Research (CBER), which is what the Bureau of Biologics was eventually called, served notice in 1990 to a major testing laboratory where agency inspections revealed serious deficiencies in blood testing practices for both hepatitis and HIV that their license would be revoked absent the necessary corrections to come into compliance with the required standards and regulations, and a plan to accomplish that had to be filed with FDA within 30 days.  Until that time the agency would not process any license applications from the laboratory’s corporation that provided for any FDA-mandated test to be done at that laboratory.  In addition, FDA notified blood and plasma centers using that laboratory that their licenses, too, would be affected if the laboratory could not or would not come into compliance.  The laboratory indeed submitted a roadmap toward compliance within the time frame required.

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Regulation of the biologics marketplace can take many different forms and must be equipped to pivot quickly to address countless threats to public health. For example, Congress appropriated $300,000 for FDA to hire 48 temporary investigators to help prevent the diversion of DBS-cleared lots of licensed Salk polio vaccine from legitimate distribution channels—those used by the six producers to ship vaccine to the states and then to public and private distributors.  FDA provided the training, oversight, and on-site assistance for the temporary staff. Though unclear how long this program would last, the agency did not encounter any missing vaccine.  A case from 2003 illustrated another turn the regulation of biologics could take. FDA’s Office of Criminal Investigations, established only shortly before, announced the discovery of counterfeit Procrit (epoiten alfa) in the marketplace. Some samples were contaminated with bacteria, and FDA laboratories found others completely lacking in active ingredient. Both the manufacturer and FDA alerted healthcare providers and patients as well to the problem and the lot numbers in question. Four months later Criminal Investigations announced three convictions in this case, though it was unclear if patients had been injured by the counterfeit product.

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Office of Therapeutic Research and Reviews

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In July 1986 FDA licensed the first therapeutic monoclonal antibody, Muromonab CD-3, to treat acute rejection of transplanted kidneys.  The biologic bound to the T cell CD-3 antigen and rapidly dispatched the T lymphocytes.

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In May 2005 new regulations took effect requiring human tissue firms to properly screen and test donors among other aspects of operations.  These also provided for swift action to be taken by FDA in the interest of public health.  Applying these new regulations early in 2006, FDA issued to a Ft. Lee, New Jersey, human tissue recovery firm an order to immediately cease all manufacturing operations.  The agency monitored the recall of all their tissues to ensure completeness of the operation.  So egregious were the deficiencies in the firm’s manufacturing practices, donor screening, record keeping, and other operations that, according to a senior agency official, “allowing the firm to manufacture would present a danger to public health by increasing the risk of communicable disease transmission.”

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In 1990, CBER approved the use of live bacteria to treat bladder cancer. BCG Live (after bacillus Calmette-Guérin), a freeze-dried suspension, was delivered directly to the bladder via a catheter to treat pathogenic cells lining the inner surface of the organ—and thus a treatment designed for earlier stages of the illness. The patient retained the product for two hours before voiding, and the treatment would be repeated for the next several weeks or months.add image of test card

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Two licenses CBER issued early in 1991 served a critically important need for patients recovering from cancer chemotherapy. Both of these, Sargramostim (rhu GM-CSF) and Filgrastim (rhu G-CSF), were genetically engineered growth factors to help regulate generation of myeloid cells (bone marrow-produced white cells). Sargramostim aided those treated for non-Hodgkin’s lymphoma, Hodgkin’s disease, and acute lymphoblastic leukemia by speeding bone marrow growth that was transplanted as part of the treatment post-chemotherapy.  Accelerating production of white blood cells in this way reduced the amount of time when the patient was most susceptible to infection by a third. Filgrastim decreased infection in chemotherapy patients by regulating the body’s neutrophil production.

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