Drug Administration Advisory Committee Research Articles

Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis.

To review selected new therapies for septic shock designed to inhibit bacterial toxins or endogenous mediators of inflammation. Scientific journals, scientific meeting proceedings, and Food and Drug Administration advisory committee proceedings. Preclinical and clinical data from trials using core-directed antiendotoxin antibodies and anticytokine therapies for sepsis and studies in animal models of sepsis from our laboratory. Ten clinical trials using core-directed antiendotoxin antibodies produced inconsistent results and did not conclusively establish the safety or benefit of this approach. Both anti-interleukin-1 and anti-tumor necrosis factor (TNF) therapies have been beneficial in some animal models of sepsis but did not clearly improve survival in initial human trials, and one anti-TNF therapy actually produced harm. Neutrophils, another target for therapeutic intervention, protect the host from infection but may also contribute to the development of tissue injury during sepsis. In a canine model of septic shock, granulocyte colony-stimulating factor increased the number of circulating neutrophils and improved survival, but an anti-integrin (CD11/18) antibody that inhibits neutrophil function worsened outcome. Nitric oxide, a vasodilator produced by the host, causes hypotension during septic shock but may also protect the endothelium and maintain organ blood flow. In dogs challenged with endotoxin, the inhibition of nitric oxide production decreased cardiac index and did not improve survival. No new therapy for sepsis has shown clinical efficacy. Perhaps more accurate clinical and laboratory predictors are needed to identify patients who may benefit from a given treatment strategy. On the other hand, the therapeutic premises may be flawed. Targeting a single microbial toxin such as endotoxin may not represent a viable strategy for treating a complex inflammatory response to diverse gram-negative bacteria. Similarly, the strategy of inhibiting the host inflammatory response may not be beneficial because immune cells and cytokines play both pathogenic and protective roles. Finally, our scientific knowledge of the complex timing of mediator release and balance during sepsis may be insufficient to develop successful therapeutic interventions for this syndrome.

Risk/Benefit Assessment of New Drugs: Perspectives of a Former FDA Advisory Committee Member

Determining the benefit/risk profile of a new drug based on information presented and discussed at Food and Drug Administration (FDA) advisory committee hearings can be at times as much subjective as it is objective. The clinical experience and expertise residing in the make-up of the committee varies considerably with respect to interpretation of reproductive and other animal toxicology data, biostatistics, epidemiology, and pharmacokinetics, as well as in specialized areas such as receptor physiology, biochemistry, and pharmacology. Since the FDA does not mandate that a precise amount of safety data be included in any new drug application (NDA) submission, it becomes the responsibility of the advisory committee to perform a risk/benefit analysis based on its knowledge of current standards of care and practice, as well as by comparisons with the existing medical and surgical approaches to a disease state. Ultimately, advisory committee members must rely on clinical judgment to reach a decision. The purpo...

Latest From Pertussis Front: Swedish Vaccine

A NEW type of monovalent toxin-inactivated pertussis vaccine has shown evidence of efficacy in a phase 2 immunogenicity trial in Sweden, investigators say. A 3-year follow-up of vaccinees compared with age-matched controls shows the vaccine to be virtually 100% efficacious in preventing pertussis, they report. While encouraging, the evidence is only preliminary, says Birger Trollfors, MD, University of Goteborg, who is directing the study. He presented data on several clinical studies with this new vaccine at a meeting of the Food and Drug Administration's Advisory Committee on Vaccines and Related Products. Safe and Immunogenic The vaccine had already been shown safe and immunogenic in trials in adults, children, and infants in the United States and Sweden. In one Swedish trial, for example, 60 children between the ages of 18 months and 23 months, without a history of natural pertussis or pertussis vaccination, given two doses of this vaccine, had pronounced

Events at Cetus cast doubt on firm's future

Cetus, one of the premier California biotechnology drug companies, is being shaken to its foundation. Just over two weeks after a Food & Drug Administration advisory committee failed to recommend approval of the company's first proprietary drug product, the much hyped but yet unproven interleukin-2, the firm was hit with a major aftershock—the resignation of Robert A. Fildes as president and chief executive officer. Speculation has spread in the financial community on the 19-year-old firm's ability to survive. According to Cetus, Fildes' resignation was precipitated by differing views regarding the company's priorities. Ronald E. Cape, a founder and chairman of Cetus, will return—only temporarily, some observers expect—to the position of CEO, which he held until 1986. Hollings C. Renton will remain chief operating officer while taking over as president. Earlier this month, Fildes, responding to the FDA committee's decision, told C&EN that delays in first-time approval for biotechnology drugs are nothin...

Additional Steps Proposed to Ensure Antiacne Drug Used Only in Appropriate Patient Population

FURTHER STEPS are being taken to prevent pregnant women from taking the antiacne drug isotretinoin (Accutane, Hoffman-La Roche, Inc). The measures include a videocassette movie for patients to see in the physician's office, warning of the teratogenic effects of the drug, and expansion of patient referral to obstetrician-gynecologists for pregnancy testing at the time of prescribing the drug. In hearing about these steps, two Food and Drug Administration (FDA) advisory committees also heard a proposal from the American Academy of Dermatology to develop a special prescription form, indicating to the pharmacist that the patient has been counseled about the risks of the drug and has had a pregnancy test. These moves represent further efforts by the manufacturer, medical organizations, and the FDA to reduce still further the fetal malformations that are likely to occur if a women being treated with the drug is, or becomes, pregnant. The drug has been

Influenza viruses do their best to thwart next winter's vaccine

A new variant of one of the two A-type human influenza viruses has emerged. Sufficiently different from the A-type viruses presently circulating in the United States, it is to be incorporated in next winter's influenza vaccine, a Food and Drug Administration advisory committee has decided. At the same time, the outbreak of avian influenza that has decimated flocks of chickens in Pennsylvania and that also has appeared in New Jersey, Maryland, and Virginia is threatening the supply of fertilized eggs on which flu vaccine manufacturers depend for growing the virus. "We don't anticipate being unable to meet our production goals for flu vaccine next year," said Frank Brandon, PhD, of Parke-Davis, Morris Plains, NJ, a division of the Warner-Lambert Company and one of the three US manufacturers of flu vaccine. "However, eggs are in short supply and this is pushing up the price." How this will affect the cost of

Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation: Panel on carcinogenesis report on cancer testing in the safety evaluation of food additives and pesticides: August, 1970

Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation: Panel on carcinogenesis report on cancer testing in the safety evaluation of food additives and pesticides: August, 1970

Recommended procedures for testing genetic hazards from chemicals, based on the induction of dominant lethal mutations in mammals.

GENETIC hazards from drugs and chemical pollutants are now widely recognized and appropriate, sensitive and economic mammalian methods for detecting and measuring mutagenic effects of chemicals have been developed. These methods are relevant to man1 and include in vivo cytogenetics, host-mediated assay, and dominant lethal assay; sub-mammalian systems are generally considered to be of ancillary value only. The Advisory Panel on Mutagenicity of Pesticides1 and the Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation2 have recommended that pesticides and food additives should be tested for mutagenicity in mammalian systems before registration. This communication recommends practical procedures for the dominant lethal assay, and indicates how these can be integrated in routine toxicological practice.

Food and drug administration advisory committee on protocols for safety evaluations: Panel on reproduction report on reproduction studies in the safety evaluation of food additives and pesticide residues

Food and drug administration advisory committee on protocols for safety evaluations: Panel on reproduction report on reproduction studies in the safety evaluation of food additives and pesticide residues

Experimental production of congenital maiformations in mammals by metabolic procedure.

Experimental production of congenital maiformations in mammals by metabolic procedure.