NYT-Results of Drug Trials Can Mystify Doctors Through Omission

[Guest guest]

> Thu, 22 Jul 2004 20:32:07 -0400

> [sSRI-Research] NYT-Results of Drug Trials

> Can Mystify Doctors Through Omission

>

> July 21, 2004

> MEDICINE'S DATA GAP

> Results of Drug Trials Can Mystify Doctors Through

> Omission

>

http://www.nytimes.com/2004/07/21/business/21drug.html?th= & pagewanted=print & posi\

tion=

>

> By BARRY MEIER

>

> pediatrician who has read medical journals lately

> might have seen articles advocating the use of the

> antifungal drug Diflucan for the treatment of

> ringworm, a childhood skin infection.

>

> But reading the extensive medical information

> enclosed in the drug's package, the same doctor

> would not learn that federal drug regulators had

> rejected Diflucan for ringworm use. Reviewing test

> data provided by the maker, Pfizer, the F.D.A.

> concluded that Diflucan was not very effective for

> ringworm - and that a child could risk liver damage

> if given high doses of the drug.

>

> It is a quirk of the F.D.A.'s labeling rules. For a

> drug's government-approved uses, the label gives

> doctors important data from clinical tests involving

> those treatments while spelling out the drug's risks

> and providing directions for administering it to

> patients.

>

> But labels are often allowed to remain silent about

> a test when the F.D.A. turns down a company's

> application for approval of a new use or a new

> patient group - as in the case of Diflucan and

> ringworm.

>

> Pfizer and the F.D.A. both say that the Diflucan

> label conforms to the agency's rules and accurately

> reflects the drug's approved uses for adults and

> children, as well as its risks.

>

> The labeling issue is another facet of an expanding

> debate over the incomplete disclosure and

> publication of the results of clinical drug trials.

> And it is one of growing importance to a number of

> physicians.

>

> The doctors worry that ambiguous or incomplete drug

> labels may lead them to prescribe drugs for

> treatments that F.D.A.-reviewed tests have shown to

> be ineffective or potentially risky. Printed

> material accompanying many drugs says the drug's

> safety and effectiveness " has not been established''

> in children - when some have been tested for

> pediatric use, with equivocal results.

>

> Until recently, several popular antidepressants

> carried the " has not been established'' language

> despite tests in children and adolescents that

> raised questions about their efficacy. Regulators

> and manufacturers have since issued safety warnings

> about those drugs amid concerns that, in a sharply

> limited number of cases, they may cause depressed

> youngsters to consider suicide.

>

> " If it has been tested, we want that to be

> reflected " on the label, said Dr. Richard Gorman, a

> pediatrician who is chairman of the committee on

> drugs of the American Academy of Pediatrics.

>

> In recent weeks, the academy and other medical

> groups have met with lawmakers to discuss possible

> legislation requiring companies to list tests of

> drugs and medical devices in a public database. And

> yesterday, Representative Henry A. Waxman, Democrat

> of California, sent a letter to Health and Human

> Services Secretary Tommy G. Thompson, urging him to

> release data from all pediatric drug trials that

> have been conducted under federal laws that

> encourage such tests.

>

> Dr. Shirley Murphy, director of the F.D.A.'s

> division of pediatric drug development, said that

> several members of an agency advisory committee that

> met in May had expressed concern that some drug

> labels omitted any reference to clinical drug trials

> that were negative or equivocal. The group included

> Dr. Gorman.

>

> " They noticed that some labels have lots of

> information and other labels didn't have

> information, " Dr. Murphy said.

>

> The issue of test disclosure on labels is not

> limited to pediatric trials. With few exceptions,

> federal law bars the F.D.A. from acknowledging that

> clinical tests were conducted, if the agency

> receives the test data as part of a drug maker's

> effort to have an existing product approved for a

> new use or category of patients and the F.D.A. turns

> down the request.

>

> Drug companies may publicly disclose such failures

> through a press release or a filing with the

> Securities and Exchange Commission, though such

> information would not necessarily find its way onto

> a label. And if a company chooses not to publicize a

> test failure, a doctor typically would not learn

> from a drug's label that such trials ever took

> place, a high-ranking F.D.A. official, Dr. Robert

> Temple, said.

>

> " If we don't agree " with the company, said Dr.

> Temple, the F.D.A.'s associate director for medical

> policy, " the doctor would not know about that. "

>

> Dr. Temple said there were exceptions, like a case

> when the trial of a drug shows a new or increased

> safety risk beyond those previously indicated on the

> label. Other exceptions include pediatric drug

> trials conducted under a federal law passed in 2002,

> the Best Pharmaceuticals for Children Act.

>

> As with an earlier law in 1997, the 2002 measure was

> passed to promote the testing of drugs in children

> because pharmaceutical companies had customarily not

> performed such trials. Instead, the practice was to

> seek approval for uses in adults, then leave it to

> pediatricians to prescribe the drugs on an off-label

> basis - as doctors are allowed to do, although drug

> makers cannot actively market drugs for such

> nonapproved uses.

>

> To encourage tests in children and adolescents, who

> may react differently than adults do to some drugs,

> the laws gave drug makers a powerful financial

> incentive - an additional six months of patent

> protection from generic competition when the

> medications were tested for pediatric use, even if

> the trials showed the drugs to be of dubious value.

>

> Dr. Gorman said he and others who helped draft the

> 1997 legislation quickly realized that they had

> failed to include a way to force a company to

> disclose all results from medications tested under

> the law. And so the 2002 law required that the

> F.D.A. release summary reports of such drug tests.

>

> Currently, reports on about 30 drugs received by the

> agency since mid-2002 are on the Web at

> www.fda.gov/cder/pediatric. There, for example, a

> browser would find the summary report on Pfizer's

> pediatric tests of Diflucan. But Dr. Gorman says he

> now believes, as a result of the antidepressant

> controversy, that the 2002 bill was not explicit

> enough.

>

> " We didn't go the next step - about what would go on

> the label, " he said.

>

> All involved agree that the laws have increased the

> amount of labeling information about the use of many

> drugs in children, like the age groups where they

> are effective or how the drugs should be

> administered. And in some cases, new warning

> information reflects safety issues that arose in

> tests, like those on packaging of some

> cortisone-based treatments for skin infections.

>

> Of the 98 drugs that qualified for testing under the

> 1997 and 2002 laws, the labels on 76 have been

> changed, F.D.A. officials said, while to date the

> labels on 22 drugs have not.

>

> The information gap between test findings and label

> information can occur even when F.D.A. officials are

> aware that doctors are increasingly using a

> medication off label for a particular problem.

>

> In the case of Diflucan, according to a test

> summary, it was the agency that asked Pfizer to run

> the ringworm trials. Regulators were concerned,

> according to that report, that pediatricians were

> turning to Diflucan because of dissatisfaction with

> an older medication and because published studies,

> some sponsored by Pfizer, reported that Diflucan was

> superior.

>

> After reviewing two Pfizer-run pediatric studies,

> the F.D.A. concluded earlier this year that Diflucan

> did not work any better than the older, generic

> drug, griseofluvin, which also poses toxicity risks.

> In the agency's report, regulators also raised

> concerns that children could face liver problems and

> other risks if doctors, seeking to treat ringworm

> more effectively, started using higher doses of

> Diflucan, which is known generically as fluconazole.

>

>

> " As some adverse events may be dose-dependent, " the

> F.D.A. document said, " it is expected that higher

> doses of fluconazole may approach dosages where the

> safety of pediatric patients may be at greater

> risk. "

>

> Dr. Murphy, at the F.D.A., said that the ringworm

> tests had not been noted on Diflucan's label because

> it did not win approval as a ringworm treatment.

>

> A Pfizer spokeswoman, Mariann Caprino, said the

> company was discussing the drug's labeling language

> with F.D.A. officials. She also said the tests did

> not raise any safety concerns beyond those already

> mentioned in the label. The F.D.A. also turned down

> an effort last year by another drug maker, Allergan,

> to get its antibacterial eye ointment, Ocuflox,

> approved for use in infants because trial data

> suggested the drug was not particularly effective in

> newborns. But the label continues to say that the

> drug's " safety and effectiveness in infants below

> the age of one has not been established. "

>

> There is little question that some drugs fail in

> pediatric trials because the tests are poorly run or

> not properly designed for children. F.D.A. reviewers

> raised the possibility of a design flaw in their

> report about Ocuflox.

>

> And while the F.D.A. review of pediatric test

> results for the popular migraine treatments Imitrex

> and Zomig found that the drugs worked no better than

> placebos in children, pediatric headache experts

> involved in those trials cited flaws in the test

> design. Dr. Gorman said it was important for all

> doctors, not just those who treat children, to know

> that trials with negative or equivocal outcomes have

> been conducted when considering the benefits and

> risks of a medication before prescribing it.

>

> Dr. Temple said that, speaking personally, he also

> believed that drug companies and medical device

> producers should voluntarily disclose test results -

> regardless of what F.D.A. rules may require.

> Otherwise, they face the risk of seeming to bury

> information.

>

> " If I was consulting companies, I would say 'Let it

> out,' " Dr. Temple said. " Now, it looks like

> something secret has been uncovered. "

>

>

>

> Copyright 2004 The New York Times Company

>

> [Non-text portions of this message have been

> removed]