Subject: FDA Rule Changes May Rush New Drugs To Very Sick Patients
Date: Published: 10/5/87 300 lines
Source:  WALL STREET JOURNAL. Copyright Dow Jones & Co. Inc. 

    Faster Action:  
    FDA Rule Changes
    May Rush New Drugs
    To Very Sick Patients
    ---
    Companies Can Sell Products
    Still in Experimentation
    To AIDS Victims, Others
    ---
    Nagging Questions of Risk
    ---
    By Marilyn Chase
    Staff Reporter of The Wall Street Journal

    When Marie Shelby died of AIDS last year, she was also a
 victim of the way drugs are developed in this country.
    The 66-year-old woman, who contracted AIDS from a blood
 transfusion, was too old to qualify for early clinical trials
 of the drug AZT, which later proved to be effective in
 prolonging the lives of certain AIDS victims.  At the same
 time, her desperate family spent about $500 in the black
 market for ribavirin, a touted drug that has yet to be proved
 useful against AIDS. 
    Now, as a result of new Food and Drug Administration rules
 that became effective June 22, pharmaceutical companies will
 be allowed under certain circumstances to recover their costs
 by selling experimental drugs that merely show promise.  The
 new procedures represent the sharpest change in 25 years in
 the way new drugs are approved, although much discretionary
 power is retained by the FDA commissioner.  It remains unclear
 whether, in the long run, the new rules will help the sick or
 hurt them.
    Supporters hope to get such drugs as AZT to very sick
 people more quickly.  They consider the changes a long-overdue
 reform of the FDA's drug-development process, which has been
 bitterly attacked as too bureaucratic, exorbitantly expensive
 and unresponsive to the needs of the sick.  Under the old
 rules, getting a new drug approved usually has taken about
 two years, while biotechnology has been churning out many
 potentially useful drugs.
    "Allowing cost recovery ...  and earlier release makes
 good sense," says Robert Levine, a Yale University professor
 of medical ethics.  Adds Peter Barton Hutt, the FDA's former
 chief counsel, who helped refine the rules:  "It shows the
 best of the regulatory process.  If you're going to entice
 small venture companies into drug development, you need a new
 mechanism because the {old} regulations drove them out.
 Companies can't afford it."
    Detractors of the new rules claim that they generate
 problems of their own.  The sick and dying won't be adequately
 protected from unproven drugs, or worse yet, from drugs that
 turn out to have lethal side effects, the critics charge.  The
 sale of unproven drugs, they say, could impede researchers'
 use of scientific method in controlled studies to establish
 the safety and efficacy of new drugs.  Selling experimental
 drugs could well mean that only patients with money will
 qualify for the latest treatments.
    Charles Moertel, a cancer consultant to the Mayo Clinic,
 condemns the new rules as "premature marketing {that}
 threatens to impair the conduct of research" and may threaten
 patients as well.  "We have the possibility of repeating the
 thalidomide disaster, but on a much larger scale."
    Under the old drug-approval system, companies could make
 experimental drugs available, free of charge, on a
 "compassionate" basis to gravely ill patients.  But drugs
 couldn't be sold until they had been through an exhaustive
 series of FDA-supervised tests, including testing that
 contrasts the reaction of large groups of patients, half of
 whom are given only placebos, harmless preparations without
 medical effects.  In the double-blind studies, neither
 researcher nor patient knows who is getting the drug and who
 is getting the placebo until the study is completed.
    Under the new procedures, companies testing a product for
 serious conditions such as Alzheimer's disease or multiple
 sclerosis can release it for treatment to doctors, or sell
 it, if they have some preliminary evidence of safety and
 effectiveness and a go-ahead from the FDA. Companies testing
 a drug for life-threatening conditions, such as advanced
 cancer and AIDS, need show only that there is a "reasonable
 basis for concluding" the product "may be effective" and
 wouldn't expose patients to "significant additional risks."
    A drug that meets these criteria -- called an
 investigational new drug for treatment, or "treatment IND" -- 
 can be sold after companies give the FDA 30 days' notice.
 Companies still conducting clinical trials must get the FDA's
 permission to sell an IND. The agency will try to restrict
 the sales price of experimental drugs to recovery of costs,
 with no profit to the seller.  It will also prohibit companies
 from advertising or promoting unapproved drugs.  Patients who
 buy unapproved drugs will still be required to sign "informed
 consent" forms outlining risks and potential benefits.
    FDA Commissioner Frank E. Young describes the new
 procedures as a way "to get breakthrough drugs to the
 American people" before final safety and effectiveness are
 proved.  "Where a person's going to die in months, and where
 patient and doctor are informed, we can take a bit more of a
 risk," Dr. Young says.  He considers the new rules a way to
 codify the extraordinary "fast-track" approval AZT got last
 year.  That drug was approved for sale to thousands of dying
 AIDS patients because of test results showing that 90% of the
 patients on AZT survived for at least a year, compared with a
 60% nine-month survival rate for patients given a placebo.
    Despite the new FDA rules, advocacy groups still are
 protesting what they see as cruelly slow drug development and
 approval.  National Gay Rights Advocates, a California public
 interest law firm, has filed a class action suit on behalf of
 AIDS patients against the Department of Health and Human
 Services, FDA and National Institutes of Health.  It charges
 that the withholding of drugs violates patients'
 constitutional rights.  California's governor, George
 Deukmejian, recently signed into law a controversial bill
 permitting drug companies to test experimental AIDS drugs in
 California without FDA approval.
    In the next few months, many businesses, particularly
 small biotechnology companies, will seek under the new FDA
 rules to rush experimental drugs to patients.  Ribi Immunochem
 Research Inc., of Hamilton, Mont., plans to seek IND status
 for an anti-cancer vaccine, while Imreg Inc., of New Orleans,
 will try to sell a drug it says may restore immune response
 in AIDS patients.  Amgen, of Thousand Oaks, Calif., is
 thinking of marketing two drugs that might restore blood-cell
 growth in patients undergoing kidney dialysis or cancer
 chemotherapy.  Xoma Inc. plans to ask FDA permission to sell
 an experimental drug for a condition called graft-vs.-host
 disease, which occurs in bone-marrow transplant recipients.
    "We intend to take advantage of whatever the new
 regulations will permit us to apply for," says Imreg's
 chairman and president, Arthur Gottlieb, who wants to recoup
 the $8 million Imreg has invested in its AIDS drug, which is
 called Imreg-1.
    These drug concerns expect heavy demand.  Just how frenzied
 the demand might be is demonstrated by the pioneer in the
 indirect marketing of experimental drugs, Biotherapeutics
 Inc., of Franklin, Tenn.  Since 1984, its founder, Robert K. 
 Oldham, has been charging patients $4,000 to $35,000 for the
 laboratory work needed to provide a range of customized
 treatments designed to stimulate the body's resistance to
 cancers.  Ostensibly, the patients are charged only for lab
 work, not for the drugs themselves.  The FDA says it is
 "monitoring the operations" of the company.
    The treatments involve interleukin-2, activated killer
 cells, cancer vaccines and monoclonal antibodies, which are
 proteins believed capable of carrying chemotherapy drugs to
 specific tumor targets.  By far its most promising treatment
 is a program of constant dosage of interleukin-2, to enhance
 the body's resistance to malignant tumors.  A well-regarded
 Biotherapeutics study, published in the New England Journal
 of Medicine in April, confirmed the findings of other
 researchers in showing that about one-third of 40 gravely ill
 cancer patients showed partial tumor remission under such
 treatment.
    Since its founding, the publicly held company has received
 some 4,000 inquiries.  It has accepted more than 300 patients
 for treatment, patients who had tried potentially effective
 traditional treatments elsewhere and who came to
 Biotherapeutics' (xxx) resort.
    Fees paid by patients tripled Biotherapeutics' revenue to
 $3.2 million for the year ended April 30.  (Nevertheless, the
 company had a $3.3 million loss.)  Dr. Oldham has ambitious
 national and international expansion plans.  His firm has
 already opened satellite labs in Memphis, Tenn.; Plantation,
 Fla.; Los Angeles; San Diego, and Newport Beach, Calif.
 Biotherapeutics is also considering cities in Japan and
 Europe.
    Hambrecht & Quist Inc., a securities firm that specializes
 in biotechnology stocks, predicts that Biotherapeutics'
 revenue will soar 120-fold in the next five years, to $385
 million, with net income reaching about $25 million by 1992.
    Results of Dr. Oldham's cancer research have been
 published in reputable medical journals, and his work has won
 some admirers among scientists.  He is a former director of
 the National Cancer Institute (xxx) so-called "biological
 response modifier" program, which develops treatments like
 interleukin-2.  In his private venture, he has demonstrated
 that the sale of experimental drugs can provide financing for
 needed research.
    But Biotherapeutics raises most of the troublesome issues
 that alarm opponents of the expanded use and sale of
 experiment (xxx) doesn't have a single proven product.
 Even with the interleukin-2 program, the remissions are
 believed to be only temporary, the drug has many toxic side
 effects and didn't benefit the majority of patients.  None of
 the vaccine and monoclonal treatments have yet shown much
 effect.
    The continuing demand for Biotherapeutics' services
 despite its mixed track record suggests how willing
 desperately sick people are to spend their own money (health
 insurance hasn't picked up any of the charges) on drugs that
 may very well not work.  And doctors now expect to see a flood
 of second-rate or inadequately tested drugs developed by
 companies that lack Biotherapeutics' scientific rigor.
    A focus of such concern is ICN Pharmaceuticals Inc. 's
 ribavirin, which has been aggressively promoted in the
 AIDS-patient underground.  It might have been considered a
 candidate for IND status last year after the company asserted
 its tests showed that ribavirin patients who suffered AIDS
 related complex, a precursor of AIDS, didn't progress to AIDS
 as often or as quickly as did patients in a control group
 given placebos.  But the study was discredited when ICN
 reseachers admitted that the placebo patients had been sicker
 than the ribavirin patients at the outset of the study.
    Pressure groups continue to promote ribavirin and to
 demand that it be sold in the U. S. FDA Commissioner Young
 hasn't yielded; ICN's application to sell the experimental
 drug was turned down on the ground that submitted data were
 insufficient.  ICN says it will reapply.  Still, drug cults are
 likely to urge the agency to release drugs on the basis of
 tests that are initially promising but flawed, critics say.
    Imreg's drug for boosting immune response to AIDS is also
 in dispute.  The company says Imreg-1 helps patients gain
 weight, slows the killing of T-cells by the AIDS virus and
 restores immune response.  But Imreg so far bases its claims
 for the drug on uncontrolled tests, without giving any
 comparison group a placebo or an alternative drug so as to
 ensure objective ]viluation.  Some researchers have sharply
 criticized Imreg's methodology.  Imreg's chairman, Dr. 
 Gottlieb, defends his experimental methods and says he now is
 conducting controlled studies and expects to +nfw results by
 the end of the year.  Still, the new FDA rules explicitly
 commit the agency to review uncontrolled studies such as
 Imreg's, or even mnbe preliminary animal and test-tube
 trials, a fact that alarms scientific purists.
    Critics worry that companies with ineffective drugs will
 settle for simply recovering their costs, without ever
 seeking to pass the rigorous tests required for final FDA
 market approval.  The FDA says companies must "actively and
 diligently" pursue final approval, but one prominent
 researcher at the National Institutes of Health fears that
 the rules "will create a secondary market for unproven
 agents."
    The FDA promises to control profiteering and the promotion
 of experimental drugs, but that could prove difficult.
 Commissioner Young concedes that the agency "doesn't have the
 expertise to do detailed economic analysis" of a company's
 profit.
    Some researchers are more worried about health
 implications than about profiteering.  Thomas Merigan, the
 chief of infectious diseases at Stanford University Medical
 Center, says making patients pay for drugs still in clinical
 trials "is very dangerous."  He adds, "It's a very small step
 to the kind of charlatanism that prevailed in pre-FDA days."
 FDA restrictions have in the past protected Americans from
 such drugs as thalidomide, the sedative that caused grave
 birth defects in Europe in the early 1960s, and Laetrile, the
 useless extract of apricot pits peddled in Mexican cancer
 clinics.
    "Today, we have drugs of much more potency and subtle
 toxic reactions," says Dr. Moertel, the Mayo Clinic
 consultant.  "They hold potential for greater benefits, but
 also greater harm and require greater protections."  For
 example, he says that the anti-cancer drug Methyl CCNU caused
 leukemia and kidney damage-reactions that didn't show up
 until very late in drug trials.
    Some of the biggest U. S. drug companies still don't plan
 to charge for experimental drugs, and that may limit the
 ability of other concerns to make money.  But demand for
 certain drugs is likely to far outstrip free sources, and
 other drugs will be available only from companies charging a
 fee.  The big companies worry that sales by small competitors
 of the very same drugs they are researching could interfere
 with their ability to do objective trials.  Patients, they
 reason, would rather buy a drug than enter a trial in which
 they have a 50-50 chance of being assigned to a control group
 receiving a sugar pill.
    Patients' advocates raise another ethical question:  To
 what degree should the affluent be able to obtain
 experimental drugs that the poor can't afford?  So far, both
 governmental and private insurers generally decline to pay
 for experimental drugs.  The wider use of such drugs, at a
 cost, suggests a two-tier system of experimental medicine:  
 limited trials for the poor, and unrestricted purchases for
 the rich.  Relatively wealthy and influential people, of
 course, may always have had advantages in the black market
 and in gaining entry to promising experimental treatment
 programs.
    Patients -- a (xxx) and otherwise -- will go to great
 lengths to avoid dying.  James Masterson, a 71-year-old
 orthopedic surgeon in Falls Church, Va., tried to get
 treatment for his lymphoma from Biotherapeutics, but at the
 company's insistence, he is trying chemotherapy first.  Still,
 Dr. Masterson believes that patient-financed research is "the
 only way to go.  Somebody's got to pay the bill.  It's either
 the taxpayer's dollar, or your money."
    Tom Jefferson, a 55-year-old San Franciscan suffering
 AIDS-related complex, spends thousands of dollars each year
 on experimental drugs available at farmacias in Mexico.  He is
 prepared to spend his money in the U. S. instead if the new
 FDA rules make the drugs available here.
    "I already do" spend the money, Mr. Jefferson says.
 "Companies aren't in it for altruism."

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