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....~ ~ tt'~~'~'~e IOIMY e~~r t ~'~~tl Ct2CYU1i/OM iM YOMIMl&M CIII ' s AioNDAT, OCTOtFR ]i,1992 Z'DEADLY OVER-CAUTION' FDA Assailed for Slow Testing of New Drugs By Carolyn Lochhead Chrwntcle WasAlnQtow Bureat Washington Charles Greene, whose fa- ther died of Alzheimer's dis- ease on Dec. 7, 1990, stood out- side the Washington headqnar• ters of the Food and Drug Ad- ministration with a small but angry band of fellow protest- ers. He had driven 17 hours from Miami to join in protesting the FAA's delay in a~proving tac- rine, a drug developed in 1988 and widely available overseas to treat Alzheimer's symptoms. About 4 miifion •:lmericans suffer from this fatal brain disorder, but there are no approved U.S.' treatments. Greene's frustrating experi- nce with the FDA approval pro- W ~ essexemplifies what critics call agency's "deadly over-cau- tion." The attempt to protect the public from the risk of unsafe and ineffective drugs carries its own risk, they co:;;end, because long delays in approving new drugs amount to.a death sen• tence for the terminally ill. ".:While we deeply empa- thize' - that's what they put in their form letters," Greene said in angry disbelief as he iecalled his "devastating" battle'with the FDA to help his father gain legal• access to tacrine through approv . ed clinical triala. The FDA subsequently ,invit- ed him to help "begin a dialogue" on how to speed drug approvals, Greene said. Bui+dit's much too. late," ht said. •"My father is dead•" Delays in approving new drugs received little more than , academic notice until AIDS pa-. tient advocates began vigorous; public protests. The FDA has. '.since accelerated the approval proce. a for such AIDS drugs as ddI'.and, ddC, but critics insist t cumbersome review pro-. •thit cxas continues to delay drug ap- provalior millions of other pea- ple suff ering from diseases less po- litically charged than AIDS. Besides Alzheimer's patients, they say, there are 8 million Amer- icans who have or have had cancer and more than 1 aiillion new can- cer cases diagnosed each year. 'They Play God' Moreover, advocates for pa-• tients say, delays are frequently not over the question of whether a drug is safe but whether it is effec- tive. Drugs often bog down in the extensive and lengthy "Phase III" clinical trials to determine effec• tiveness. "They play God with us," said George Rhenquist, president of the Families for Alzheimer's Rights Association. Decisions about whether to prescribe drugs that are safe but not yet proven effective are better made by pa- tients and their doctors, not the FDA, he said• "Why should they have control over the lives of our loved ones?" FDA chief David Kessler says his agency has learned from AIDS patient advocates that it must has- ten approval of drugs to treat fatal illnesses. "The riskiest thing we can do is to be unwilling to take any risks," he said in a recent inter- view. Kessler pointed to new policies to speed drug approvals that were announced by the agency in April. First recommended by the Council on Competitiveness headed by Vice President Dan Quayle, the key change was the "accelerated approval" or "fast tracking" of new drugs for patients with such life-threatening illnesses as AIDS, cancer, Alzheimer's and cystic fi- brosis. "The pendulum has swung," Kessler said. do little to help the smaller compa- nies that play a large part in the development of new drugs in this country. Moreover, they say, the plan fails to address the underly- ing flaws in the lengthy regulatory process. "I see patients wrestle with this all the time," said Eugene Schon- feld, president of the Chicago- based National Kidney Cancer As- sociation, who himself has kidney cancer. "I see some of them give up, and say; 'OK, I can't fight it anymore. Pm going to die.' They have to fight the disease. That's bad enough. But to have to fight the bureaucracy is intolerable." On the average, development of a new drug takes about a decade and costs $231 million. In 1991, fi- nal FDA reviews alone had averag- ed 2% years. One drug for arthritis was approved last year after near- ly nine years under FDA review; another for angina was reviewed by the agency for eight years. Kidney Cancer Drug In the 3% years it took the FDA to approve the drug Interleukin 2, about '35,000 kidney cancer pa- tients died. The only known treat- ment for metastatic renal cell car- cinoma, a fatal kidney cancer, IL2 group, reported that an FDA offi- cial, requesting anonymity, recent- ly conceded that the issue is "very touchy" because "homosexuals are well organized and I think the FDA would be hesitant to take them on; the cancer and Alzheimer's pa- tients are not as well organized." Beverly Zackarian, who heads the cancer patient advocacy group CAN ACT, nearly died from ad- vanced ovarian cancer during a desperate struggle to obtain an un- approved drug that was the lead- ing treatment in Europe but had languished for 10 years in U.S. clin- ical trials. "Mere is no 'accelerated ap- proval' for cancer drugs," Zackar- ian said. "There is no 'parallel. track.' Those are AIDS specific. We're still on the outside looking in." Although the FDA has long of- fered "expedited access" for some unapproved cancer drugs, she said, the amount of paperwork re- quired makes many doctors hesi- tate to use the mechanism for all their patients - and many pa- tients do not even know the drugs exist Drup-Review Fees Early this month, Congress passed a bill allowing the FDA to charge drug companies fees for re- viewing new drugs as a way to speed the approvai process. Kes- sler said his goal is to hire 600 new examiners and cut:drug 'review time in half. Critics say that although the measure may help large firms that can afford to pay fees expected to run as high as $2i9,000 for each drug approval application, It will 'We Can't Wait' FDA advisory committees for cancer drugs still appear to be- `If you're screaming for someone to throw you a rope, and I insist on stress-testing it firstfor your sqfety, you're dead' - SAM KAZRAN, CUMPETITIVE ENTERPRISE INSTITUTE had already been approved in nine European countries. The therapy is risky: The odds of being helped by the drug are about one in four, and the odds of dying from It are about one in 25. But the disease it- self is always fatal. The FDA has sped approvals of AIDS drugs, said James Driscoll, a nationally known Bay Area AIDS patient advocate, "but if you look at other areaa like cancer, you have situations that are much more disastrous." The Competitive Enterprise In- lieve, Zackarian said, that "people with cancer can somehow wait. We can't wait. Cancer is always a life-threatening illness. There is no ZI-D such thing as a touch of cancer." c~ Peter Barton Hutt, former Wzib chief counsel at the FDA, said that c~ although the FDA might move ~ quickly each year on one or two high-profile drugs, average ap• ~ proval time has held fairly steady ~ since 1970 at 2% to three years. "It ~ takes a long, long time," he said. ~ `"That has not changed, and I don't ~ think it will." stitute, a Washington advocacy •, FDA:' PapeA4 QAL 1

A4 San ;.Francisco (Zhronictt: ***** (PA's Testing Process for New Drugs Assailed From Page 1 He likened the approval pro- cess to a balloon: "You can squeeze it in the middle and make it very thin, down to three months or six months. Then what happens is that the rest of the balloon gets bigger - the time for other drugs gets longer." The problem, some economists say, is that the FDA is geared to err on the side of caution out of fear of a calamity such as the thalidomide disaster. Thalidomide, a sedative introduced in Germany in 1957 but not approved in the United States, caused thousands of terrible birth defects. Yet studies by economist Sam Pelzman of the University of Chi- cago and others have shown that long delays in drug approval may kill more people than they save. For example, some physicians estimate that during the FDA's nine-year ban on beta blockers, a treatment for heart attacks, as ~.ay as 50,004 people died who ~ght have been saved by the "We've seen photos of thalid- omide babies," said Sam Kazman of the Competitive Enterprise In- stitute, "but we've never seen any photos of the victims of the FDA's beta blocker ban." More and More Data "Caution sounds like a neat thing," says Kazman. "Except that if you're drowning, and you're screaming for someone to throw you a rope, and I insist on stress- testing it first for your safety, you're dead. Over-caution in pub- lic health can be as deadly as un- der-caution, and right now, unless the whole system is changed, over- caution is still the main thing on the FDA's mind." Martin Delaney, head of Pro- ject Inform, a San Francisco AIDS patient advocacy group, says that the FDA has reformed iuelf in "genuine and substantive ways" but that officials there "are often intimidated by consumer protec- tionists and some of the congress- men, who beat them up every time a drug gets through too quickly. et nobody ever beats up the agen- y in Congress for drugs that get chrough too slowly." CAN ACTs Zackarian agrees. "It's Congress who pulls the FDA's strings," she said. "If one person is in jured by a drug or thinks he or she is in jured, they call their con- gressperson, who then calls the FDA, and the commisstoner has to answer for it So naturally every- body becomes risk averse. The fact is, when people die by the thou- sands because the FDA has not ap- proved a drug, nobody calls Con• gress. And I think that is the reall crux of the problem." 'The Alternative Is Deathr A proposal by Representative Tom Campbell, the lame-duck Palo Alto Republican who lost his pri- mary bid for a Senate seat, would lower the efficacy standard for drugs to treat life-threatening ill- nesses. "When the alternative is death, I think the standard should be different," Campbell said. "The objection to a drug that hasn't been proved effective loses its meaning when the alternative is d..thg „ ~ The bill, tied up in the House Energy and Commerce Commit- tee's Subcommittee on Health and the Environment, died when Con- gress adjourned last week. Chris Cox, R-Newport Beach, said he will reintroduce the bill next year. The FDA's Kessler maintains that follow-up testing is vital to pa- tients. "We have to insist that we gen- erate data so in the end we know whether (a drug) works," he said. `The whole conditional (accelerat- ed) approval mechanism will only work if we're willing to have that kind of follow-through." Without a requirement of proof that a drug works, he said, companies would have no incen- tive to conduct conclusive tests. "If you can go out tomorrow and mar- ket Compound X," he said, "what's the incent're to do all the trials, invest in all the research and dem- onstrate that It works?" Yet what this view suggests, Kazman said, "is that people and their physicians don't care about efficacy, and so the government has to require it." He and others call this reasoning "nonsense" and contend that patients, doctors and drug companies all face powerful incentives to find drugs that work. Many observers contend that no meaningful progress will be achieved without reforms that ad- dress underlying flaws in the regu- latory process. Had the stringent toxicity stan- dards that the FDA is applying to tacrine been applied to the AIDS . treatments AZT, ddI and ddC, said Driscoll, "none of the AIDS drugs ~ C)nfy 1=iri,9,t300, ",:cbmpcurids_,.; ;j _ ~pr+sdrntccl teshng ~ .,. Y:'sinxeedto:~ human tests Lk ~~Human ~` ctrnicai testing: Investigationai New Drug ,.i lication EZ ; with FDA. Tests divided into three phases involving progressively more subjects. One out of five drugs that pass preclinical tests and enter human trials ultimately obtains FDA approval. One out of 5,000. . 'drugs completes the process from laboratory to FDA , approval.. THE DRUG APPROVAL PROCESS START: Square = i year Praclinical testing: A compound is subjected to iaboratcxy and aninwl testing that tries to determ'sne whethsr the compound is biologically active and safe. .W Avemges 3.5 years. Human dinical testing, phase one: The initial human testing, primarily to detennine safety and do . Trials involve a small number of~ealthy volunteers and are relatively short, toking about one year. Phase two: Controlled tests using 100 to 300 volunteers, primarily to determine efiec- tiveness. Simultaneous animal and h;rnan tests also continue to assess safety. Averages two years. Phase three: Extensive testing of 1,000 to 3,000 volunteers, divided into treatment and control groups, to confirm the results of eariier efficacy tests and identify side effects that may occur infrequently. Averages three years. New drug application: Documentation, which may be more t:ion 100,000 pages, filed with Food and Drug Administration ofhx completion of 4W- human tests. Application covers drva stnxture, the scientific rationale and- pu se of the therapy, predinical stu ies, all human testing results, formulation and production details, a:,d proposed label7i.5 Takes average years to process. MCI EDAApproval:..,'- .• _ Tota}time.iram (aborotory'tvfinal: - aPProval bverages:l2 years.°• ' : • . • 'Source: hanna&tit7mlNlanotarn,n:rsAssodofron; cppfordrees bosed on 199D es/imale by raUs Uni.ersiry%Ccnhrlortho%*af 'va9 oevekPClew. could have been approved. This in- dicates that there has been no fun- damental change in FDA thinking ... that they are temporarily adapting to the pressures of AIDS activism but the whole system has not changed." WeII-Informrtd Patients Partial reforms, such as "ex- panded access" programs in which drug companies give away experi- mental drugs to selected patients, Driscoll said, are usually limited to well-informed, well-educated and affluent patients, and access to clinical trials is often limited to pa- tients who live near a handful of sites in large cities. Kazman suggests chaaging the FDA's veto power over new drugs to a system of certification. The agency would continue to review safety and efficacy but would al• low unapproved drugs, clearly la- beled as such, to be avaixable by prescription. The ultimate choice of whether to use a drug would be left to patients and their doctors. He says this approach woula bring pharmacology in line with the rest of medical care. FDA ap• proval, he says, is not reqnired of surgical methods, yet people do not worry about podiatrists doing in-office heart transplants