FDA Eases Rules on Drug Testing to Help Desperately Sick Patients : Public health: Critics say the agency’s rush to make available promising medications is compassionate but bad science.
In this dangerous world, the agency entrusted with balancing the scales between risk and therapy in medicines is the Food and Drug Administration. It holds America’s health and nutrition in its hands.
For years it has protected a vulnerable public from dangerous drugs, food additives and quackery that caused maladies ranging from impotence to cancer, birth deformities to death.
But for the last decade or so this federal watchdog has been bending its rigid rules, formulated over a century, to release essentially untested but promising drugs in the name of compassion to those in danger of dying of AIDS, those losing their minds to Alzheimer’s disease, those withering from some rare cancers, those suffering from the debilities of multiple sclerosis and muscular dystrophy.
The same agency sometimes is caught in the political nowhere. Recently it has been criticized for not requiring long-term testing of silicone breast implants on one hand and for not approving a French abortion pill on the other.
It is at the same time trying to make sense of food labeling--low fat, low salt--much to the displeasure of the food industry.
It is again surrounded by charges that some pharmaceutical companies had withheld reports of side effects that surfaced only when those companies had to answer charges in court that their products had hurt unaware users. Targeted are the sedative Versed and the sleeping pill Halcion, leading some critics to say the FDA should be given subpoena powers to extract any damaging reports from drug manufacturers.
Through the years, the FDA’s powers have been increased, almost always on the heels of scandal.
Here, politics and science collide, public good and profit-making co-habitate, morality and selfishness find a home, in one eclectic agency, scattered in 25 to 30 buildings in Washington and suburban Maryland.
The FDA is a creature both of Congress and the growing social awareness of the 20th Century. It did not come on the scene as anything more than an awkward contrivance, a barrier to insensitive manufacturers.
It was created by legislators stung by muckraking magazine writers from Colliers Weekly and a book by Upton Sinclair called “The Jungle.” The book, while fiction, portrayed the meatpacking industry as a filthy one that threw all sorts of offal into sausages.
That was not Sinclair’s intent. He was trying to expose the exploitation of immigrant labor in the food industry. He said of his efforts, “I aimed at the public’s heart and I hit it in its stomach.”
“It wasn’t until 1906 that there was a Food and Drug Administration,” recalls Dr. John Parascandola, head of the Library of Medicine at the National Institutes of Health.
People, including doctors, had grumbled about the adulteration and lack of standards in largely imported drugs since the Mexican-American War when surgeons could not count on the effectiveness of the medications they were administering to wounded soldiers, says FDA historian John Swann.
“There were some specific laws that dealt with the importation of opium and things of this sort and there were some state laws.” says Parascandola. “But in terms of a broad federal bill that regulated food and drugs, the first one was in 1906. And it was fairly limited.” Coincidentally or not, 1906 was the year of publication of Sinclair’s book.
Which means that for more than 100 years this young democracy ate, drank and self-medicated itself without much oversight on the businesses that provided it with its food, its beverages and its therapeutic dosages. Which, in turn, meant that innumerable people died needlessly.
In the late 1800s all people had to do to obtain opium was to declare it their habit.
“Today,” says Parascandola, “we have people pressing the FDA to be more liberal, in a sense, about letting (some therapeutics) onto the market and even accusing the FDA of delaying them. . . . “
But the new procedures are logical. “It is an interesting change, and when you’re dealing with AIDS, it’s not the same thing as talking about putting a new sedative on the market,” Parascandola says. “People are desperate. They’re dying. AIDS, so far as we know right now, means 100% mortality.”
The sedative he is referring to is thalidomide, a drug which was effective in countering morning sickness in pregnant women, and in the early 1960s led to thousands of deformed babies in Europe and some in the United States.
There might have been more except for Dr. Frances Kelsey, a dedicated FDA pharmacologist who blocked the way because she was not satisfied with the safety assurances from the manufacturer.
Now the FDA closely monitors not only the results and procedures of the private laboratories that do the nation’s drug testing, but the clinicians who administer experimental drugs to patients and report the results. When field investigators find sloppy or inconsistent performance, a laboratory or a doctor can be banned from further tests on any drug.
The FDA has always had trouble getting the public’s attention, although it monitors, more than any other federal agency, except perhaps the Department of Agriculture, the public’s daily appetite for medicine, food and even mascara.
It was the scandal in the meatpacking industry that led to the legislation creating the FDA out of the old chemistry laboratory under the Agriculture Department. The next major overhaul came in 1938. This time the stimulus was the drug sulfonamide, one of the first wonder drugs.
No one questioned the effectiveness of sulfa, which was administered by injection.
But in an effort to make it more available to children, the next logical step was an oral drug. That meant the sulfa had to be dissolved into a syrup.
One enterprising American firm began distributing such a concoction in 1937. It used diethylene glycol as the solvent. Nobody bothered to look it up, but diethylene glycol is poisonous. Before the elixir was banned, some 107 Americans, most of them children, had died.
That scandal focused the public’s attention again on how open the drug market was to error and fraud and led to the passage of the 1938 Food, Drug and Cosmetic Act that greatly increased the FDA’s powers to make sure that drugs were safe.
The thalidomide scandal of the late 1950s and early 1960s left thousands of deformed babies in Europe, most of them in Great Britain and Germany, where a West German firm discovered the drug and licensed an American firm to market it in the United States.
But the American firm never got the chance. It did however distribute the drug to doctors for clinical investigation, and the FDA was not aware of the extent. It turned out, says Kelsey, now age 77, that more than 1,000 doctors had been given the drug to try on their patients.
“Yet, the new drug application that came in to us suggested that only 40 or 60 had it,” she recalls. “Those who had the drug hadn’t kept very accurate records. They were sure it really wasn’t very necessary.”
The result was that only 17 babies in this country were affected before the FDA and Kelsey stepped in. Seven of these came from drugs obtained abroad. There were “nine other cases of deformities in the U.S. with some links to thalidomide,” says the FDA’s John Swann, “but they were not as clear-cut as the others.”
Nonetheless, that scandal led to a congressional investigation and the 1962 legislation that greatly increased the FDA’s powers to ensure that drugs be not only safe but effective as well.
So 1906, 1938 and 1962 were the pivotal points. Each was preceded by enough public outrage to keep the caldrons of concern boiling in Congress.
For the last decade it has been public concern again that led to the new thrust in making experimental drugs more rapidly available to the disabled and dying and to streamline the approval process.
Dr. Randy Wycoff, who heads the FDA office coordinating the AIDS drug effort, says there are two general approaches for these new moves to get drugs through the FDA to the patients who need them.
“It (the FDA) took the spirit of the existing law and formalized it into a new regulation. It specifically allows promising products for serious and life-threatening diseases to be made available prior to approval. . . . “
The first approach is for Treatment INDs which allows some patients to be treated with an Investigational New Drug before it has cleared all the testing hurdles.
Of the 24 Treatment INDs allowed to date, he says, eight have been for AIDS-related drugs, the rest to other ailments for which there are no alternative therapies available.
Some of those include Alzheimer’s, multiple sclerosis, muscular dystrophy, some rare and untreatable cancers such as hairy cell leukemia, Lou Gehrig’s disease or amyotrophic lateral sclerosis, Parkinsonism and respiratory distress syndrome in infants, “basically any disease that is seen as resulting in death or severe impairment for which there is no other treatment.”
There are new approaches up for consideration, modeled on the procedure the FDA used in allowing the treatment with Videx, an antiviral drug which shows promise against AIDS and advanced Human Immunodeficiency Virus disease by those who have exhausted the benefits from or who cannot any longer tolerate the pioneer drug AZT.
Videx or DDI (didanosine) was approved for use in appropriate patients, but not without criticism. In early trials the drug was shown to increase the body’s production of certain white cells, which are important in the immune response.
It was developed by the National Cancer Institute and has been licensed to Bristol-Myers Squibb for marketing. But the study of the drug was shortcut to bring it on line more quickly. FDA Commissioner David Kessler says, “There is somewhat of a leap here, but patients are dying and we think the extrapolation makes a lot of sense and is in the patients’ interests.”
The FDA decided to proceed after trials on 2,500 AIDS victims. One critic saw it as a bad precedent. “We will see more drugs approved on the basis of very little data,” says Dr. Deborah Cotton of Boston’s Beth Israel Hospital and the FDA advisory committee that approved the drug, “and we will have less ability to know how to choose among them or how to use them in combination.”
Compassion versus tried-and-true traditional science.
The new procedures bypass the double blind that has been the benchmark of drug testing for decades. In double blind studies, one group is given a drug and another is given a placebo. To ensure against bias, the investigators are blind to which patient is which.
Under the new approach, all patients are given a new drug or a combination of drugs and the results are measured against a historical control group that has been given a different drug in earlier trials.
All of these new procedures are coming on the scene with a sense of urgency created by the some 10 million AIDS patients in the world, a number expected to rise to 40 million by the end of the decade. But not only AIDS.
The FDA recently approved a drug for use in Alzheimer’s patients that increases the production of a vital brain chemical, acetylcholine.
At the same time the FDA has greatly accelerated the approval of drugs. The first human studies of DDI were in 1988, and it was approved for wider use this year, sprinting through a process that could have taken at least twice as long.
New drug treatment can come even more quickly. A Treatment IND can be approved in 30 days. But, if an individual doctor with a patient suffering from a life-threatening disease hears of an experimental drug and his patient wants it, he can frequently get permission and the drug in the space of a few phone calls.
“None of what we’ve talked about,” says Randy Wycoff, “takes the agency away from its commitment to assured safety and effectiveness. We’re still doing that. . . .
“We also recognize, as do many others, that people with life-threatening diseases who have no alternative therapies are willing and their physicians are willing, in some cases, to take the additional risk.”
