Approval of Zalcitabine

Date: June 22, 1992
Source: Food and Drug Administration (FDA)

HHS Secretary Louis W. Sullivan, M.D., today announced that the Food and Drug Administration has approved the AIDS drug zalcitabine, commonly known as ddC. It is the third drug licensed specifically for use in treating the human immunodeficiency virus, the cause of AIDS.

Zalcitabine was approved for use in combination with the first approved AIDS drug, zidovudine -- or AZT -- as a treatment option for adult patients with advanced HIV infection who show signs of clinical or immunological deterioration.

This drug approval represents another step forward for patients with AIDS," Dr. Sullivan said. "Zalcitabine has been rapidly developed, tested and reviewed through the cooperative efforts of scientists in the National Institutes of Health and FDA, academia and the pharmaceutical industry.

Early clinical trial data have shown that increases in CD4 cells (immune cells) were somewhat greater and more sustained in patients treated with the combination of zalcitabine and zidovudine than in those who received zidovudine alone as initial therapy. An increase in CD4 cells is believed to indicate that the body's disease-fighting capability has been at least transiently enhanced.

At present, however, there are no study results demonstrating enhanced survival, lowered incidence of opportunistic infections or decreased progression of HIV infection for patients treated with the combination of zidovudine and ddC.

ddC is the first drug approved under the principles and procedures of FDA's proposed accelerated drug review policy, endorsed by the White House Council on Competitiveness and announced by the Vice President on April 9. The proposal also provides for prompt removal of the drug from the market if further review determines the therapy to be ineffective.

Four studies investigating the clinical usefulness of zalcitabine are continuing, to verify the clinical benefit of the combination therapy.

This new drug is not a cure," said James Mason, M.D., assistant secretary for health and head of the Public Health Service, "but it constitutes an important addition to the expanding group of antiviral drugs currently available, including AZT and ddI, for treating people with AIDS."

The most severe side effects observed in individuals taking zalcitabine have been in the form of neurological complications, sometimes causing tingling and pain in the hands and feet. In controlled clinical studies, 10 to 12 percent of patients discontinued treatment because of these complications. Other side effects included pancreatitis (inflammation of the pancreas), rash, oral ulcers, decreased blood platelet (blood clotting elements) counts and abnormal liver function. The side effects of the combination of zalcitabine and zidovudine are about the same as those that would be anticipated with either drug, each with significant side effects alone.

"This approval marks an important change in FDA's drug review policy," said FDA Commissioner David A. Kessler, M.D. "In this way, we can approve drugs that are both safe and effective as quickly as possible."

The pharmacological action of zalcitabine, a chemically synthesized compound originally discovered for its antiviral activity by scientists at the National Institutes of Health in Bethesda, Md., appears to be its ability to prevent the AIDS virus from replicating or reproducing before T-cells (immune cells) are infected, thus preserving the cells' immune function.

The drug, manufactured and distributed by Hoffman La Roche of Nutley, N.J., is administered orally every eight hours in combination with AZT. Sold under the trade name HIVID, it is expected to be commercially available immediately.

Both FDA and NIH are Public Health Service agencies within HHS.

Milestones in ddC Approval Process

October 30, 1991 -- NDA filed with FDA by Hoffman-La Roche
November 1991 - April 1992 -- FDA actively working with Hoffman-La Roche to discuss data, work out additional analyses. Additional study and clinical trial data solicited by FDA and the company.
April 21, 1992 -- Antiviral Drug Products Advisory Committee recommends approval of ddC in combination therapy.
April - June 1992 -- Continuing meetings between Hoffman-La Roche and FDA on labeling. Hoffman La Roche committed to series of studies to further demonstrate efficacy and better define appropriate clinical use.
June 19, 1992 -- ddC approved by FDA.
June 22, 1992 -- Secretary Sullivan announces approval.
First drug approved since the Vice President announced FDA's accelerated drug approval process.
Process incorporates use of surrogate endpoints to determine efficacy.
Process allows for approval to be withdrawn if further review determines the therapy to be ineffective.

Drugs approved in normal process take an average of 10 years in development and 2 years for FDA review of the NDA. ddC's development took four years and the FDA review, including intensive discussions and soliciting more data, took 8 months.