Food and Drug Administration, U.S. Department of Health and
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
work 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 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 surrogate
endpoints is an important tool to speed promising drugs to
people who desperately need them."
FDA's decision to approve DDI followed the recommendation 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 benefited throughout its development from a
number of innovative measures FDA has taken to expedite the
review and availability of potentially promising experimental
For example, large-scale 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
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
- 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
- recombinant human alfa interferon for the treatment of
- fluconazole for the treatment of candidiasis and cryptococcal
- erythropoietin for the treatment of the severe anemia
sometimes associated with zidovudine therapy.
FDA is one of the Public Health Service agencies within HHS.