ddI Receives Additional Approval

Date: October 1, 1992
Source: Food and Drug Administration (FDA)

Wider access to and lower doses of didanosine (ddI), the anti-HIV drug, have been approved by the FDA for patients previously treated with zidovudine (AZT).

The following will be used to answer questions.

Didanosine (trade name Videx), manufactured by Bristol Myers Squibb Co. of New York, was approved by FDA in October 1991 for patients with advanced HIV infection who are intolerant to AZT or whose health has significantly deteriorated during AZT treatment. Based on CD4 cell count data obtained in early trials, as well as an interim evaluation of CD4 cell count data from a controlled trial, this early approval was given in order to make the drug available for treatment of HIV-infected individuals for whom there are no alternative therapies. At that time, data were not available to demonstrate actual clinical benefit -- a slowing in the progression of HIV disease or a reduced number of AIDS-related complications.

A two-year controlled clinical trial, sponsored by the manufacturer and the National Institutes of Health has compared patients who had received prior AZT treatment and were switched to one of two doses of ddI, with patients who continued AZT treatment. The median duration of prior AZT therapy was 13.7 months. Results of this trial published in the New England Journal of Medicine on August 27, 1992, have shown that the ddI-treated patients took longer to develop AIDS-related illnesses than those on continued AZT therapy.

These new data were submitted to FDA in response to the agency's request for a follow up to its original approval of the drug.

The study provided no information on the optimal time at which patients should be switched from AZT to ddI. The new FDA-approved physician package insert for ddI describes the studies participants and results. Physicians can than interpret the information in the context of the individual patient.

These data also show that a lower dose of ddI than is currently used is associated with lower toxicity -- most significantly, a lower rate of the drug's major side effect, pancreatitis. The lower dose was demonstrated clearly to be no less effective than the higher dose studied.

Other studies comparing doses of ddI, as well as a study of ddI versus AZT in patients who have not received prior antiretroviral therapy, are ongoing.

Department of Health and Human Services HHS NEWS October 9,1991

HHS Secretary Louis W. Sullivan, M.D., today announced the Food and Drug Administration's approval of dideoxyinosine (ddI) -- an antiretroviral drug -- for treating patients at advanced stages of infection with the AIDS virus. ddI is approved for use in adult and pediatric AIDS patients who are intolerant to or whose health has significantly deteriorated while on zidovudine (AZT), the only other approved treatment for infection with the AIDS Virus.

ddI's approval in the United States coincides with the drug's approval by the Health Protection Branch (HPB) of the Canadian Department of National Health and Welfare. Officials at FDA and HPB conducted an historic joint review of ddI which allowed medical reviewers from both nations to work in close cooperation in analyzing ddI's database.

Dr. Sullivan said, "Today's action offers a new weapon against the AIDS virus itself, and provides new hope to those who could not benefit from AZT. The Food and Drug Administration, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute and the Bristol-Myers Squibb Company are to be commended for the extraordinary work they have done in ensuring the rapid testing and evaluation of this drug."

Dr. Sullivan also emphasized the significance of the joint U.S. Canadian review of ddI. He said, "Today's approval shows that cooperation promotes the health and welfare of both the Canadian and American people. I salute the Honorable Benoit Bouchard, Minister of Canada's Department of National Health and Welfare, and the other Canadian health officials whose hard word helped ensure the success of this effort."

ddI was approved on the basis of data derived from early clinical trials conducted by its sponsor, Bristol-Myers Squibb Co. of New York, N.Y., the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. These data demonstrated ddI's positive effects on an immunologic, or surrogate, marker, in patients at patients at advanced stages of infection with the AIDS virus.

These trials primarily evaluated ddI's effect on increasing the number of CD4 helper cells, a surrogate marker for a clinical determination of effectiveness. CD4 helper cells are white blood cells important in the immune system that are destroyed by the AIDS virus. Healthy individuals normally have CD4 helper cell counts of 1,000 or more, while those at advanced stages of AIDS infection usually have counts of 200 or less. FDA has accepted the conclusion of many researchers that an increase in CD4 cell counts indicates a beneficial effect on a patient's immune system and general health.

FDA Commissioner David A. Kessler, M.D., pointed out that FDA's decision to approve ddI on the basis of a surrogate endpoint rather than on traditional clinical endpoints, such as, survival is another example of FDA's work to expedite the development of AIDS drugs.

"This means that drug approval decisions may be reached at an earlier stage in the process than if clinical endpoints were used, because clinical endpoints often take more time to develop," Dr. Kessler said.

Dr. Kessler emphasized that although the data base is adequate for approval, the use of surrogate endpoints means that the agency has less information about ddI's long term safety and efficacy than it would normally have from clinical endpoints. "More clinical studies must be done on ddI to better understand how well ddI works, and data from these studies must be applied to its future labeling," Dr. kessler said. "Nevertheless, in the face of the AIDS crisis, FDA believes that use of the surrogate endpoints is an important tool to speed promising drugs to people who desperately need them."

FDA's decision to approve ddI followed the commendation made this past July by a majority of the members of the Antiviral Drug Products Advisory Committee. The committee of non-government experts was concerned about the lack of traditional clinical endpoint data for ddI, but concluded that the surrogate endpoint data, when combined with the absence of any approved drug for AIDS patients unable to take AZT, warranted approval for the drug.

"FDA has reviewed and analyzed the data on ddI in six months -- a short time for such a complex application," said HHS Assistant Secretary for Health James O. Mason, M.D., who heads the Public Health Service. "The new drug application for ddI was submitted in April 1991. Along with other promising AIDS drugs, ddI has benefitted throughout its development from a number of innovative measures FDA has taken to expedite the review and availability of potentially promising experimental AIDS therapies.

For example, large-scare clinical trials and expanded access protocols for ddI were sanctioned by FDA in September 1989. Under these protocols, more than 2,500 persons with AIDS or AIDS Related Complex have been enrolled in clinical trials.

In addition, more than 15,000 other patients have received the drug through the Treatment IND or open study protocols that were designed to allow access to patients who could not participate in the clinical trials because they could not tolerate AZT or had already failed on the drug.

ddI is known to produce serious adverse reactions in some patients and its use requires careful monitoring. Among the adverse effects experienced are inflammation of the pancreas, which can be fatal, and painful nerve damage. These toxicities may be reversible if detected early and if the drug is discontinued.

The use of ddI as a drug to treat AIDS was co-discovered by Drs. Samuel Broder, Hiroaki Mitsuya and Robert Yarchoan in the National Cancer Institute. The group first identified the activity of ddI against the AIDS virus in the laboratory in June 1985 and initiated the first clinical trial in adults in August 1988. The discovery of this drug derives in part from a longstanding research program in tumor-causing viruses in the National Cancer Institute.

Initial studies of ddI in children were carried out by Dr. Phillip Pizzo and colleagues at the National Cancer Institute.

The drug will be marketed by the Bristol-Myers Squibb Co. under the trade name "Videx."

This is the ninth drug approval for treatment of AIDS or an AIDS related condition. The other eight are:

  • Foscarnet for the treatment of sight-threatening CMV retinitis * Zidovudine (AZT) for treating infection with the AIDS virus * Ganciclovir for the treatment of CMV retinitis
  • Aerosolized pentamidine for use in preventing the occurrence and recurrence of Pneumocystis carinii pneumonia
  • Injectable pentamidine for the treatment of Pneumocystis carinii pneumonia
  • Recombinant human alfa interferon for the treatment of Kaposi's Sarcoma
  • Fluconazole for the treatment of candidiasis and cryptococcal meningitis
  • Erythropoietin for the treatment of the severe anemia sometimes associated with zidovudine therapy.
FDA is one of the Public Health Service agencies within HHS.