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

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In 1988, a new research division was established within the FDA's Center for Biologics Evaluation and Research (CBER), the Division of Cytokine Biology. Cytokines are proteins that have multiple cellular functions, including effects on the immune system, antiviral activities, and the ability to differentiate between cells. Cytokine biology has the potential to further the development and review of therapies for diseases like AIDS and cancer.

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Research in this division focuses on improving existing quality control tests for biologics by finding ways to improve animal tests or to switch them to in vitro (test tube or cell culture) tests. The biological testing laboratory Biological Testing Laboratory is within this division, and it has two sections: the reference reagents section Reference Reagents Section and the animal testing and quality assurance section. The reference reagents section Animal Testing and Quality Assurance Section. The Reference Reagents Section establishes the U.S. Reference, or standard the  standards of preparation used by the FDA and manufacturers when performing official tests required for biologics. The animal testing and quality assurance section is responsibility Animal Testing and Quality Assurance Section is responsible for testing the potency and sterility of biological products and does safety tests on vaccines.

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The Division of Blood and Blood Products performs research on the preparation, preservation, and safety of blood and blood products, and methods for testing the safety, purity, potency, and effectiveness of these products when used therapeutically. There are seven labs in this division: cell biology, transplantation biology, blood bank practices, retrovirology, hepatitis, plasma derivatives, and cell componentsCell Biology, Transplantation Biology, Blood Bank Practices, Retrovirology, Hepatitis, Plasma Derivatives, and Cell Components. 

Division of Virology

Vaccine testing and research is done by this division , including in their four labs: DNA virus research, respiratory virus, pediatric diseases, and retrovirusVirus Research, Respiratory Virus, Pediatric Diseases, and Retrovirus. 

Division of Cytokine Biology

This was the newest division of CBER in 1989, having only been formed in 1988. It was an outgrowth of the Division of Virology. Cytokines are proteins that have multiple cellular functions, including effects on the immune system, antiviral activities, and the ability to differentiate between cells. The division is responsible for conducting regulatory review and research on biological response modifier agents (medical treatments derived from substances naturally found in the body), which may hold promising treatments for AIDS, cancers, and infectious diseases. Laboratories under the Division of Cytokine Biology include cellular immunology, cell biologyCellular Immunology, Cell Biology, and molecular immunologyMolecular Immunology. 

Division of Biochemistry and Biophysics 

This division is an interdisciplinary group who studies molecular and cell biology, pharmacology and toxicology, biochemistry and biophysics, and combines basic science with regulatory activity. There are seven labs in this division: molecular immunologyMolecular Immunology, biochemistryBiochemistry, analytical chemistryAnalytical Chemistry, biophysicsBiophysics, cellular Cellular and molecular biology, molecular pharmacologyMolecular Biology, Molecular Pharmacology, and chemical biologyChemical Biology. 

Division of Bacterial Products

This division has seven labs within it, including pertussisPertussis, allergenic products, bacterial toxins, bacterial polysaccharides, mycobacteria and cellular immunology, mycoplasma, and cellular physiologyAllergenic Products, Bacterial Toxins, Bacterial Polysaccharides, Mycobacteria and Cellular Immunology, Mycoplasma, and Cellular Physiology. 

Allergenic Products 

Allergenic investigations by the FDA Bureau of Biologics in 1978 focused on standardized in vitro and in vivo assays of allergenic potency. The former in vitro tests under development included radial immunodiffusion, isoelectric focusing, and allergen coupling compared to radioactive or enzyme-labeled antibody. The in vivo assays under study were based on the skin tests used in allergic patients as well as the immunogenicity of allergenic extracts following their use in the immunotherapy of allergic disease.

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By the early 1980s, the FDA Bureau of Biologics had a laboratory on mycoplasma, but scientists had been investigating mycoplasmas since before the DBS moved into Building 29 in 1960for decades. Mycoplasmas are single-celled bacteria lacking a cell wall and are able to penetrate other cells; they constituted constitute a challenging source of contamination of cell cultures. A DBS regulation in 1960 required manufacturers to test for mycoplasmas in human viral products that relied on cell cultures. As mycoplasma tests advanced over the years, the testing rules changed accordingly. With the emergence of hybridoma technology to generate biological products (in which a target antigen is injected into a mouse, a resulting antibody-producing cell is harvested from the spleen, and the splenic cell fused with a tumor cell to produce the desired antibody), mycoplasmas found their way into the new products from this technology, such as monoclonal antibodies. The Bureau of Biologics’ rulemaking and research interests by the 1980s had thus had shifted to controlling mycoplasma contamination of the products developed from this newer approach to biologics production.

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Almost simultaneously with the transfer of biologics from the NIH Division of Biologics Standards to the FDA Bureau of Biologics in 1972 were two key changes in the regulation of blood products. First, all federally licensed blood banks had to test for the hepatitis-associated antigen (HAA), a discovery , which had been discovered within the previous decade, and exclude from donation any blood testing positive. Also, the FDA Bureau of Biologics licensed a new test for HAA, much more sensitive than previous tests, and Bureau staff continued their research into test improvements.

Inspections of intrastate blood collection establishments in 1974 indicated several widespread problems: slightly less than half the inspections revealed failure of the blood collection centers failed to adequately establish donor suitability, ; about the same percentage demonstrated of centers had problems with their blood collection techniques, ; and half exhibited of the centers performed faulty hepatitis testing. To get a better handle on the massive effort to regulate the blood and blood product industries, the Bureau of Biologics initiated a database , called the Blood Establishment Inspection and Registration System—finalized in 1976—to monitor the thousands of annually renewed blood collection centers' registrations and licenses, the biennial inspections of several thousand facilities, the compliance history and progress with the firms, and impact of regulatory changes.

A 1979 action against another problematical blood bank had to negotiate the need to compel compliance against the realities of providing a vital service. A blood bank that was the largest supplier to South Florida , distributing distributed annually 140,000 units to 54 hospitals—90 percent hospitals—90% of the need blood products in that area, . But it was doing so without much regard for following the required good manufacturing practicesGMP, as documented in recent by FDA inspections. Thus, enjoining Enjoining the firm from further operations until they could come were in compliance would deprive a large population of crucial biologicals. Thus, the agency FDA and the blood bank reached a consent decree of permanent injunction, in which the blood bank agreed to bring its operations into compliance immediately, as well as bringing in an outside expert toward making all to help make all of the necessary changes for GMP compliance long-term. At the same time, the government prevented an interruption of a crucial supply of biologicals with an expectation that corrections would be made quickly.

In mid-1986, Biologics the Bureau suspended the licenses of four blood banks in Texas, Michigan, Missouri, and Kansas whose operations varied so significantly from required good manufacturing practices GMP as to represent a danger to health. Each was inadequately supervised and the staff insufficiently trained, in addition to other problems. Lacking a license, they were not allowed to operate until FDA determined they were in compliance, and the Commissioner had the discretion to revoke their licenses in the absence of corrections.

Prompted by concerns with the transmission of the virus that causes AIDS virus, FDA launched an intensive inspection program of all blood banks and plasma centers in 1988. Over 11 percent 11% of the facilities were found to have significant enough violations to prompt a regulatory response. These problems included the processing of blood suspected of contamination with the AIDS virus, although there were no cases where blood or products confirmed to be so contaminated were released. During this program inspections of American Red Cross (ARC) blood banks in Nashville and Washington, D. C. indicated operational errors leading to the release of unsuitable units of blood and blood products, errors that continued despite corrections. So, in 1988 FDA and ARC signed a voluntary agreement in which the latter would improve operations across the nation by establishing closer better oversight of regional operations by national headquarters, standardizing operating procedures, and monitoring more closely computerized information to prevent release of unsuitable blood.

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 blood testing laboratory where agency inspections revealed serious deficiencies in blood testing practices for both hepatitis and HIV. The laboratory was warned that their license would be revoked absent if they did not make the necessary corrections to come into compliance comply with the required standards and regulations, and ; a plan to accomplish that goal had to be filed with FDA within 30 days.  Until Until that time the agency , FDA 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 . 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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Recalls are an important part of regulating biological products. Some are initiated by the company; others proceed from at FDA’s request. The Bureau of Biologics took part in its first biologics recall in FDA in 1973 when a Philadelphia firm issued a voluntary recall for immune serum globulin that was distributed in vials containing 25 percent 25% less product than labeled. After the transfer to FDA, the The Bureau utilized a new enforcement approach to violative biologics, employing FDA-supervised voluntary recalls. Their employment , which resulted in non-sterile serum albumin linked to multiple cases of septicemia, hypo-potent hypopotent HAA, misbranded bacterial antigen, and other unlawful biological products being efficiently and thoroughly taken out of distribution and followed up by the agency. 

Inspections and enforcement actions by the Bureau of Biologics grew increased such that by 1974 they conducted 800 inspections of establishments holding biologics licenses. Office of Biologics’ regulations Regulations called for at least one inspection annually for licensed establishments, though that was adjusted to a biennial basis in 1983 to give Biologics the Bureau more flexibility to manage its resources and to better align better with inspection frequency for drug and medical device establishments. The Bureau was responsible for testing lots of antitoxins, vaccines, blood products, diagnostics, and other biologics prior to release. In its first full year in the FDA, Bureau scientists tested over 6200 lots of these products and rejected 144. Often the problems were due to hypo-potencyhypopotency, but pyrogenicity, lack of sterility, and other issues were responsible as well. Nearly two dozen blood and allergenic products were recalled under Bureau supervision for pyrogenicity and other problems; one of these had led to a hepatitis outbreak. This The outbreak , traced to up to three was traced to  lots of plasma protein fraction in from an Indianapolis hospital blood bank, and was attributed to inadequate pasteurization, and all . All of the firm’s plasma protein fraction and normal serum h H was recalled.

The agency Bureau issued over 300 Regulatory Letters to establishments in 1974—mostly to blood facilities. These official The letters identify identified violations and indicate stipulated a deadline for correction before the party is ; if the deadline was not met, the facility would be subject to court proceedings. The Bureau of Biologics also obtained a decree for the destruction of improperly stored lots of influenza vaccine and tetanus toxoid and secured a permanent injunction against multiple facilities of a Florida plasmapheresis firm in major and repetitive violation of regulations for the collection and processing of plasma. Two years later FDA obtained the first permanent injunction against an intrastate blood bank, which enjoined it from operating in violation of the Federal Food, Drug, and Cosmetic Act. Inspections at an Ohio hospital blood bank on two occasions revealed serious deficiencies which threatened both blood donors and recipients, and each visit prompted increasingly severe warnings if non-compliance with regulations continued. After a third inspection revealed ongoing and hazardous operations outside of the regulations, the agency secured the permanent injunction, which allowed the hospital to operate only in emergency situations and to receive blood from outside sources.    

Adverse event reporting has had a checkered history across all FDA medical product centers. In October 1994, CBER amended the biologics regulations to require that manufacturers of licensed biological products must report to FDA, within 15 working days , all serious and unexpected adverse events relating to their products; any significant increase in the frequency of serious but expected reactions; periodically, . Periodically, they must report all other adverse experiences ; and biologic distribution information.

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FDA issued the first license for human leukocyte typing sera in 1975, making it broadly available for use in identifying potential donors for organ transplants and transfusions.  The following year the Bureau established a histocompatibility testing laboratory to provide quality assurance testing and to create reference standards for anti-human leukocyte typing serums proposed for commercial release. In 1982, the Bureaus of Biologics and the Bureau of Medical Devices agreed, and the FDA Commissioner approved, that leukocyte typing sera would be delicensed and regulated as an in vitro diagnostic under the Medical Device Amendments of 1976.

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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 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 an order to immediately cease all manufacturing operations to a Ft. Lee, New Jersey, human tissue recovery firm an order to immediately cease all manufacturing operations.  The . The agency monitored the recall of all their tissues to ensure completeness of the operation.  So 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 “Allowing the firm to manufacture would present a danger to public health by increasing the risk of communicable disease transmission.”

Therapeutic Research and Regulation 

The FDA Bureau of Biologics scientists investigated a biological used to prevent tuberculosis, BCG vaccine, in animal models for possible application in cancer immunotherapy, following on from results from other researchers.  

Late in 1980, Biologics Bureau scientists developed tests that might be applied to viral-based diseases of the central nervous system, including subacute sclerosing panencephalitis.  They They found a way to measure small amounts of viral antibodies in the cerebrospinal fluid (CSF).  In In a study published in Lancet involving a control group plus about two dozen people suffering from schizophrenia, tests of CSF for eight common viruses, including measles, mumps, and herpes simplex, they found a substantial disproportion of cytomegalovirus in the CSF compared to serum—a suggestive link but certainly one needing further study.

The FDA Office of Biologics Research and Review (OBRR), what biologics the Bureau was known as is in the 1980s, ramped up the facilities and understanding necessary to address the regulatory aspects of advances in genetic engineering, including nucleic acid sequencing and gene cloning technology. Guidelines soon followed for recombinant DNA products, such as monoclonal antibodies, which were finding their way into licensable commodities such as in vitro blood tests and in vivo diagnostics and therapeutics.

FDA licensed two recombinant interferons, Interferon alfa-2a and Interferon alfa-2b for the treatment of hairy cell leukemia in 1986, the first of their kind. They were shown to arrest or regress the disease, reduce disease complications, and lengthen survival, with relatively untoward mild side effects. OBRR continued its research into the structure and function of interferons, and more than a dozen were awaiting awaited further study, though their therapeutic promise had still not been assessed. Discovered decades earlier as naturally occurring anti-infective proteins in the body, recombinant DNA techniques made sufficient quantities of interferons available for research and therapeutic application.

The Center for Biologics Evaluation and Research (CBER) licensed recombinant Human Tissue Plasminogen Activator on November 13, 1987, to limit heart damage by dissolving blood clots if administered soon after a myocardial infarction. Two years later the Center approved Eminase (anistreplase), another bioengineered blood clot dissolving product to help prevent damage following a heart attack. It was designed to afford quicker for faster administration and circulate circulated in the system body longer than other treatments in this class.

On June 1, 1989, CBER approved epoetin, a treatment for anemia due to chronic kidney failure. This was a copy of erythropoietin, the protein responsible for stimulating reproduction and growth of red blood cells in bone marrow. Blood transfusions were the typical approach to treating severe anemia, though those came with a host of risks and problems. Though Although this approval was limited in scope, other studies were underway to assess epoetin in several other applications linked to anemia, such as anemia-induced cancer chemotherapy and AIDS.

Botulinum Toxin A, an injectable treatment for eye conditions such as strabismus, was licensed by CBER in 1989.

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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 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.

CBER licensed the first drug genetically engineered product drug to treat adult kidney cancer specifically, aldesleukin, in May 1992. The drug produced some serious side effects , to an extent that it had to be administered intravenously only in a hospital by clinicians experienced in cancer chemotherapy. However, at this time about 10,000 patients died of renal cancer annually, and aldesleukin reduced tumors in 15 percent 15% of those treated, and in 4 percent 4% of patients the  tumors disappeared for nearly two years.

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In July 1993, CBER issued the first license for a biologic treatment for multiple sclerosis (MS), Interferon beta-1b. This also was the first biotechnological product licensed under FDA’s accelerated approval regulations. Since there was no approved therapy for MS this was designated a priority review.  At At the time there were an estimated 250,000-350,000 cases in the U. S.  Also, though Americans with MS. Also, although a biologic was subject to the provisions for licensing under the law, the review was carried out collaboratively by CBER and the Center for Drug Evaluation and Research, which provided clinical review expertise. A two-year study of 338 patients showed that interferon, in comparison to a placebo, decreased flare-ups by 30 percent 30% and reduced brain lesions as captured by MRI scans by 20 percent20%. However, it did not change the course of the disease. The Peripheral and Central Nervous System Advisory Committee recommended approval of Interferon beta 1-b for relapsing-remitting MS by a 7-2 vote. Four months after the advisory committee vote CBER licensed the biologic. Under accelerated approval regulations the firm had to carry out post-marketing studies to investigate interferon’s slowing or preventing progress of the disease.
    
In December 1997, CBER scientists Drs. Tamas Oravecz and Michael Norcross and several other researchers in the Division of Hematologic Products, along with Dr. Mark Gorrell of the University of Sydney, published results of research they conducted that uncovered how immune cells are directed to respond to infections. A protein known as CD26, found on the surface of certain white blood cells, could activate or inactivate chemokines. The authors looked at the relationship between CD26 and several chemokines and found that “target cell recruitment into inflammatory sites may depend both on the extent of CD26 activity on chemokines and on the maturational status of the responding cells.” This new understanding of CD26, the authors believed, suggested a pathway toward new therapies for various infections and other diseases where chemokines have a role.

CBER licensed Herceptin (trastuzumab) in September 1998, . It was a monoclonal antibody that represented a new approach to the treatment of metastatic breast cancer. Bioengineered from an altered antibody in a mouse, the monoclonal antibody bound to HER2, a protein that regulates cell growth that is found on certain normal cells. This ability to bind to the protein enabled the antibody to interfere with tumor cell growth. In metastatic breast cancer, about 30 percent 30% of the tumors express excess HER2, so this would be useful only in patients with tumors of that character. FDA approved Herceptin alone for those who received little benefit from chemotherapy or as a first-line treatment when used in combination with paclitaxel.

CBER and the NIH's National Cancer Institute (NCI) began a collaborative research and clinical project in 2001, the Clinical Proteomics Program, to make a comprehensive study of all proteins in living cells and apply this to the clinical care of cancer patients. Drs. Emanuel Petricoin in CBER and Lance Liotta of NCI led the effort, which was funded for three years at about $1 million annually. The two groups had already developed new or improved analytical technology for the purpose, have identified more than 130 different proteins found in several types of cancer. Using the latest microscopic procedures to biopsy cells pre- and post-treatment would allow the team to analyze the impact of different therapies on tumor protein patterns. Among other benefits the The Program hoped to achieve was earlier ability to diagnose cancer, a better sense of toxic and beneficial effects from the lab before clinical application, and improved understanding of tumors at the protein level, and better treatments for cancer patients.  The The following year, the Proteomics collaborative reported preliminary results in The Lancet on diagnostic developments they uncovered by using protein patterns found in normal serum and that collected from an ovarian cancer patient.

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