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100 Years of Biologics Regulation

Around the turn of the last century, diphtheria patients were routinely treated with antitoxin derived from the blood of horses. There were no central or uniform controls in place and the antitoxin was often manufactured in local plants. In St. Louis, that combination had tragic consequences. Thirteen children died of tetanus in 1901 after being treated with diphtheria antitoxin made from the blood of a tetanus-infected milk wagon horse named Jim.

Soon after this and a similar tragedy in Camden, N.J., involving deaths and injuries related to a tainted biological product, Congress enacted the Biologics Control Act. July 1, 2002, marks the 100th anniversary of the law, which gives the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) authority to regulate biological products and ensure their safety.

Biologics are medical products derived from living sources. They include vaccines, blood and blood derivatives, allergenic patch tests and extracts, tests to detect HIV and hepatitis, gene therapy products, cells and tissues for transplantation, and new treatments for cancers, arthritis, and other serious diseases.

Here are some key research contributions in biologics over the last century.

Polio Vaccine

In the early 1900s, Americans were frightened of polio for good reason. Polio is a highly contagious disease that paralyzes or kills its victims, and children are especially vulnerable.

In 1908, Austrian biomedical researcher Karl Landsteiner determined that polio is caused by a virus rather than bacteria. Eight years later, thousands of New York City residents fled their homes to avoid a polio epidemic that hit the area in 1916.

Bacteriologists Ida A. Bengston (1881-1952) and Alice Evans (1881-1975) were the first women employed on the scientific staff of the Hygienic Laboratory, predecessor to the National Institutes of Health. Ida Bengston was particularly noted for her studies of bacterial toxins, especially the discovery of the organism Clostridium botulinum, which caused a paralytic disease in chickens. Alice Evans identified undulant fever as a human form of abortive fever in cattle and traced its transmission to contaminated milk. This hastened the spread of the pasteurization movement in the United States.

Ruth Kirschstein, M.D., deputy director at the National Institutes of Health, remembers living with her parents near a park when she was 10 years old and the country was in the midst of another polio epidemic in 1936.

"They would take me to the park every day in the summer and sit down and say, 'don't talk to anybody, don't go near anybody, don't do anything because you might get polio.' That was the thing people were most scared about-having their children end up in iron lungs. We've gotten rid of that, and it's just absolutely marvelous."

During the early 1950s, researcher Jonas Salk developed a killed virus polio vaccine. Salk tried the vaccine on volunteers, as well as himself, his wife and children. All those who received the vaccine developed antibodies to polio and no one got sick. In 1954, nationwide testing of Salk's vaccine began with mass inoculations of school children. A million children participated in the tests, making it the largest clinical test of a drug or vaccine in medical history. The Salk vaccine was found to be safe and effective. However, the tests came to a halt after more than 200 cases of polio caused by the vaccine suddenly occurred. It was determined that two batches of the vaccine produced by Cutter Labs contained live poliovirus and were responsible for the outbreak. Eleven people died as a result.

In 1955, the U.S. Surgeon General recommended that all polio vaccinations be suspended until a thorough inspection of each manufacturing facility and review of the procedure for testing vaccine safety had been completed. Manufacturing resumed after stricter standards were adopted, and more than 4 million doses of the Salk vaccine were distributed by August of that year.

In the late 1950's, Albert Sabin theorized that a weakened, live-virus polio vaccine would provide longer-lasting immunity. The Sabin vaccine, which was inexpensive and administered orally, became the primary weapon for polio prevention in the United States by the end of the 1960s. Ironically, because the vaccine contains weakened live forms of the virus that can mutate, some people develop polio after taking this vaccine.

Now, with polio on the brink of eradication throughout the world, the Salk inactivated vaccine is the only product recommended for routine childhood vaccination in the United States.

Measles Vaccine

In 1964, a global epidemic of rubella, also known as German measles, spread to the United States. About 12.5 million cases were reported that year, and 20,000 infants were born with birth defects as a result.

In 1966, former CBER directors Paul D. Parkman, M.D., and Harry M. Meyer, Jr., M.D., reported that they had developed the first effective experimental vaccine for rubella. The researchers prepared a weakened, live vaccine for human testing and inoculated 34 children. None of the children developed rubella, nor did they transmit the disease to their unvaccinated playmates. By 1988, only 225 cases of rubella were reported in the United States.

Testing vaccines and serums for purity and potency: The National Institutes of Health played a leading role in the development and regulation of biologic products from 1903, when the 1902 Biologics Control Act became effective, until the transfer of these regulatory functions to the FDA in 1972.

Pertussis Vaccine

Whooping cough (pertussis) vaccine had been available since 1915, but results from its use were not entirely satisfactory. There were many concerns regarding the potency of the vaccine. A CBER researcher named Dr. Margaret Pittman helped improve the vaccine in 1944. By 1949, manufacturers were able to sell whooping cough vaccine approved on potency as well as on safety and sterility.

CBER licensed the vaccine that is in use today on July 31, 1996. It is the first acellular pertussis vaccine for use in infants and children two months of age and older for the primary series of immunizations. This new vaccine contains only the parts of the pertussis bacterium thought to be important for immunity. So it protects infants against whooping cough while causing fewer side effects than the whole-cell pertussis vaccines that were previously on the market.

Blood and Plasma Products

From the 1950s through the 1970s, evidence indicated that the blood obtained from commercial blood banks carried a greater risk of hepatitis transmission. This led to more careful testing, and to increased regulation of blood to further protect the blood supply.

Researcher Emily Emmart worked in the NIH's Division of Biologics Standards in the early 1960s. This division was the home of the Laboratory of Biologics Control from 1955 until 1972, when the regulation of biologics was transferred to the FDA.

According to John Finlayson, Ph.D., associate director for science in CBER's Office of Blood Research and Review, "Hepatitis loomed very large. Most of us talked about serum hepatitis and that it was a very large threat post-transfusion," says Finlayson. "We had no tests for hepatitis A, no tests for hepatitis B, and of course, hepatitis C had not even been discovered. So that was a very big challenge, and there was also the challenge that there could be post-transfusion bacterial infections."

During World War II, there were two major concerns-providing clean blood and preserving blood plasma. But when soldiers were transfused, they had no guarantee of receiving clean blood because none of the tests used today were available.

Furthermore, because plasma was pooled for preservation, one infected donor could contaminate an entire batch. In response, an American chemist named Dr. Edwin Joseph Cohn led a team that devised a method called fractionation. This separated the individual proteins out of plasma. The resulting protein products, known as plasma derivatives, can be given in response to specific medical needs and with a high degree of confidence that they are safe.

AIDS and the Blood Supply

Safeguards over the years for blood donor screening and blood collection, processing, and testing led to increased confidence and perhaps a relative degree of complacency in the United States concerning safety of the blood supply. Thus, the scientific and health-care community, as well as government agencies and the public, were not prepared when AIDS emerged with full fury in the 1980s.

Blood transfusions became suspect, and improved screening tests for donated blood were necessary to protect the American people. CBER researchers and the blood and medical product industries responded to the challenge. The first test kit to detect HIV, the virus that causes AIDS, in donated blood was licensed in 1985. Inspections of blood banks were increased to ensure compliance with strict screening and processing procedures. Now, highly sensitive and specific nucleic acid-based tests allow the presence of hepatitis and HIV to be detected more rapidly.

Challenges for the 21st Century

Recent advances in technology have opened the doors to many other exciting areas in science. For example, gene therapy now allows us to actually alter the genetic makeup of a cell. Philip Noguchi, M.D., director of CBER's Division of Cellular and Gene Therapies, says, "Instead of giving a person interferon-which is a protein used to treat certain cancers and other diseases-why not give the person the gene and then his own body will actually start to make the protein, and might never have to replace it again? That's one of the very intriguing theories of gene therapy."

Xenotransplantation, the transplantation of animal cells, tissues or organs into a human, offers new hope for an added source of organs. New vaccines are being developed and modified as new discoveries teach us more about the human immune system. And the genomics revolution has scarcely begun. The study of gene structures is leading to potentially effective treatments for a variety of serious diseases, including cancer, diabetes, and heart disease.

"New biological products such as vaccines and therapeutics have already improved the health of the public," says Kathryn Zoon, Ph.D., director of CBER. "The blood supply has never been safer. And, as we move through the 21st century, our strong leadership in science-based regulation, coordinated research, and the use of partnerships will continue to assure that safe and effective new biological products reach the public."

This article was adapted from the CBER publication "Commemorating 100 Years of Biologics Regulation."

In memory of Harry M. Meyer, Jr., M.D., director of the FDA's Bureau of Biologics, 1972-1987. Dr. Meyer and Paul D. Parkman, M.D., developed the first licensed rubella virus vaccine.