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Executive Summary

Merck's Recombivax HB (DNA-produced hepatitis B vaccine) was approved by FDA on July 23, within five months of the submission of a license application, and within seven years from the time of the initial characterization of the hepatitis B virus gene. The relatively short development period from first discovery to FDA approval began in 1979 when Chiron scientists and collaborators characterized the genetic make-up of the hepatitis virus. According to Chiron press material, in 1979 the biotechnology firm determined the "specific genes responsible for making the surface antigen of the virus." Two years later, Chiron successfully designed and constructed recombinant DNA molecules that could direct the formation of the HBV antigen in both bacteria and yeast. Animal studies with the recombinant vaccine began under the supervision of Merck in 1982, and clinical testing began only three years ago. Merck plans to introduce Recombivax in January 1987. The firm said it is waiting until January so that it can produce enough of the recombinant vaccine to meet potential demand. Merck said it will continue marketing its plasma derived hepatitis B vaccine Heptavax B after the introduction of Recombivax. However, the firm said that the market will ultimately determine whether it is feasible to make both products available. Merck is pricing Recombivax so that it can be a replacement product for Heptavax, without undercutting the per treatment cost of the existing product. The company said the price of the recombinant vaccine will be "comparable" to Heptavax. A standard three-dose regimen of Heptavax costs approximately $110. Merck noted in press material that more than 1 mil. people have been vaccinated with Heptavax in the U.S. since it became commercially available in 1982. However, FDA comments on the approval of Recombivax indicate a sizeable domestic market may still exist. According to FDA, "only 3 to 30% of various groups at high risk of contracting hepatitis B have been vaccinated using the older, plasma-derived vaccine." The low use, FDA explained in a press release, "may result from fear of getting AIDS from a plasma-derived product, since most of the donors of the plasma used to make the older vaccine are at high risk for AIDS as well." FDA emphasized that "there is no doubt that the plasma-derived vaccine is safe and its processing kills the virus that causes AIDS, but the new lab-made vaccine should further reassure high-risk groups that they can be safely vaccinated." FDA estimates that approximately 200,000 new hepatitis B infections occur in the U.S. each year. The plasma-derived product was an immediate success when it was first launched. Three months after the initial introduction of Heptavax, Merck reported that it distributed 600,000 doses of the vaccine, enough to innoculate 200,000 people. The early demand for the vaccine subsided however during the 1983-1984 period due to AIDS contaminations fears. Merck said that use of the vaccine escalated in 1984 after the Centers for Disease Control announced that hepatitis B vaccinees were not at risk of getting AIDS from the vaccine. Merck said sales of Heptavax in 1985 outpaced sales in both 1982 and 1983. At the July 23 approval press conference, FDA and Merck emphasized that Recombivax and Heptavax are comparable in terms of safety and efficacy. "In clinical studies," Merck said, "Recombivax HB has been shown to induce protective levels of antibodies against hepatitis B virus infection in more than 90% of healthy individuals who received the required three-dose regimen," Merck said. Labeling for Heptavax states that in one clinical trial, "protective antibody developed in 96% of vaccine recipients." The two other trials discussed in the labeling found protective rates of 96% and 87%. Both vaccines are indicated for immunization against infection caused by all known sub-types of hepatitis B. Heptavax labeling states that "vaccination is recommended in persons of all ages, especially those who are or will be at increased risk of infection with hepatitis B virus." Merck noted that Recombivax studies found that "response to the vaccine was dependent on the age of vaccinees; 100% of 73 children one to ten years of age developed antibodies while seroconversion (antibody production) rates ranged from 95 to 99% for 453 adults between the ages of 20 and 39, and 91% for 56 vaccinees 40 years of age and older." Recombivax was also studied in "newborn children of mothers who are chronically infected with the hepatitis B virus," Merck said. "Efficacy in preventing chronic hepatitis B infection was 94% among 93 infants studied at six months and 93% among 57 infants studied for nine months." Heptavax was also studied in infants born to mothers infected with hepatitis B. It carries that indication. Discussing the safety of Recombivax, Merck said the vaccine "was found to be generally well-tolerated in clinical trials in more than 3,000 vaccinees. No serious adverse reactions attributable to the vaccine have been reported during the course of these clinical trials." Merck reported that "among 1,252 healthy adults, who were administered the new vaccine and then monitored for five days after each dose, the most frequent complaints were local reactions at the injection site, including soreness, itching, and swelling." Additional reactions "with an incidence equal to or greater than 1% included fatigue, headache, fever, malaise, nausea, diarrhea, pharyngitis, and upper respiratory infection." The approval of Recombivax follows closely behind the approval of three other biotech products. FDA's Office of Biologics cleared Roche's Roferon-A and Schering's Intron A brands of alpha interferon for hairy cell leukemia June 4 ("The Pink Sheet" June 9 p. 3). Ortho's monoclonal Orthoclone OKT3 was approved June 19 for the treatment of acute rejection in renal transplants ("The Pink Sheet" June 23, p. 3). Biotech approvals, in fact, outnumber new molecular entity approvals through the first seven and a half months of 1986. According to FDA's monthly approval lists through June, the agency has approved two NCEs in 1986: Wyeth's Orudis (ketoprofen), approved Jan. 9 ("The Pink Sheet" Jan. 13, p. 4) and Burroughs-Wellcome's Nix (permethrin 1% lotion) approved March 31 ("The Pink Sheet" May 5, T&G-5).

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