Subject: REVIEW & OUTLOOK (Editorial):  First Do No Harm
Date: Published: 12/21/87 128 lines
Source:  WALL STREET JOURNAL. Copyright Dow Jones & Co. Inc. 

    REVIEW & OUTLOOK (Editorial):  
    First Do No Harm

    The year 1987 may prove to be a watershed in this
 country's attitude toward new-drug development and the needs
 of seriously ill patients.
    The most positive event was the rapid approval of AZT, the
 only drug shown so far to significantly retard the progress
 of AIDS. AIDS has forced both researchers and regulators to
 face the stark fact that patients who are suffering and dying
 can't wait and won't wait for the system to operate as it has
 for 25 years, as a bureaucratic leviathan.  Sign-carrying AIDS
 demonstrators on the streets of Manhattan made the point
 plainly:  "The FDA is killing us."
    Partly in response, the agency, under the direction of
 Commissioner Frank Young, set regulations this year to make
 promising experimental drugs more quickly available to
 patients.  The state of Massachusetts has received permission
 to use the first such drug, a new immune globulin to protect
 pregnant women exposed, for example, to German measles.  In
 another sign of progress, the legislature of California
 created the country's first state-based drug-approval system.
 It is intended to fast-track the research ongoing in the
 state's many biotech companies.  Seven drugs, four for AIDS
 and three for cancer, have already been submitted to the
 program for consideration.  We felt like a voice in the
 wilderness when we started to write about the therapy-denial
 issue three years go, but these real gains show it is
 becoming widely recognized.
    ---
    Still, 1987 was also the year of TPA, the now-famous
 clot-dissolving drug for use on heart-attack victims.  About
 500,000 Americans die annually of myocardial infarction.  (So
 far, some 21,000 Americans have died of AIDS.)  The core of
 the controversy that developed over TPA stems from the fact
 that while a federal research team, involving 20 private and
 academic U. S. research centers, proved and hailed TPA's
 ability to open blocked coronary arteries in April 1985, the
 FDA system didn't approve the drug for general use until last
 month.  During that 2 1/2-year interval, according to the
 American Heart Association's estimates, 3.75 million heart
 attacks occurred, resulting in 1.35 million fatalities.
 Absent some compelling reasons, such a delay seems to us
 ethically indefensible.
    We have of course written extensively on this issue,
 particularly after an advisory committee recommended
 disapproval of TPA for general use last May.  We wish to know
 exactly how such decisions were made, from fear they reflect
 procedures that are also delaying drugs for other dread
 diseases.  New insight is now available, since the FDA has
 recently responded to our Freedom of Information filings for
 background material on the May meeting.
    "Safety was the first and most important issue," eight
 members of the advisory committee wrote in an Aug. 12 letter
 to this newspaper.  The letter cited figures that TPA might
 cause bleeding into the brain and that at one dose level the
 incidence of bleeding "may be as high as 4% or as low as 1.5%
 to 2%...  ."  That higher and indeed disturbing rate of 4% is
 based on a statement made at the public hearing by the FDA's
 Dr. Raymond Lipicky, who said, "In that 350 patients, 16 had
 intracranial bleeds."  That is 4.6%.  In a heated exchange, the
 drug's sponsor asserted that Dr. Lipicky's denominator was
 wrong, that the 16 bleeds occurred not in 350 cases but in
 more than 1,000.
    The material recently supplied by the agency summarizes
 the results of a large number of TPA studies.  In no study
 does TPA display an incidence of cerebral hemorrhage above
 2%.  Asked about this in an interview last week, Dr. Lipicky
 now says the decision was based on such issues as TPA's
 dosage and manufacturing process.  He dismisses the bleeding
 percentage as irrelevant:  "I can't remember how the
 denominator came to pass.  But that wasn't the critical
 issue."
    ---
    Safety, indeed, may not have been the determining issue,
 to judge by another FOI document, an 84-page evaluation of
 TPA's research results performed by the agency's assigned
 medical reviewer, Dr. Abraham Karkowsky.  Prior to approval,
 no one outside the agency saw Dr. Karkowsky's analysis.  Had
 it been made public, the agency's intent to delay TPA would
 have been obvious.  The plain fact is that the FDA staff
 wanted more studies done with more patients.  In a word,
 delay.
    Specifically, Dr. Karkowsky challenges whether opening a
 blocked artery saves the victim's heart:  an "agent which
 causes thrombolysis should be required to demonstrate a
 salutary effect on the outcome in patients...  ."  Similarly,
 in the agenda questions the FDA provided the advisory
 committee.  Question six:  "There has been no large randomized
 study comparing rt-Pa with any alternative treatment.  If clot
 lysis is a persuasive endpoint for potential effectiveness,
 how does the lack of a controlled database affect your
 ability to render a risk/benefit assessment?  "
    The point being made here is that there had been no large
 study in which TPA was "randomized" -- that is, given to some
 heart-attack victims, while others in the placebo group get
 nothing other than standard care.  The NIH team in charge of
 the first TPA study said explicitly in its April 1985 report
 that it could no longer ethically withhold TPA from any
 patients in its study.  So some 2 1/2 years later we discover
 that Dr. Karkowsky didn't like NIH's decision; he wanted data
 to match a large Italian study that led the FDA to approve
 another blood-clot dissolver, streptokinase.  In the Italian
 placebo group, 758 people died.
    Under the current system, the ethics of this process is
 never raised.  There is no provision for discussing the
 immediate needs of critically ill patients.  We are glad to
 see the beginnings of awareness with the AZT decision, the
 new experimental regulations and of course the ultimate
 approval of TPA. Even so, at the center of the FDA's world
 one finds "databases," not patients lying in beds.  Too often
 the quest is for the perfect statistical study, not aid to
 the ill.  TPA is only one example.  AIDS patients have raised
 this issue to a matter of national concern.  And, if they had
 the time or energy, so too would cancer patients or victims
 of Alzheimer's disease.  "What about us!" these people are
 screaming at the FDA. This country's patients deserve an
 answer.

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