| Ilena Rose 2006-09-29, 4:31 pm |
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http://www.nytimes.com/2006/09/29/b...agewanted=print
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September 29, 2006
New Sense of Caution at F.D.A.
By ANDREW POLLACK
A federal advisory group last week derided the Food and Drug
Administration as a feckless watchdog unable to protect consumers from
unsafe medicines. But try telling that to drug company executives,
investors and analysts.
Many of them say the F.D.A. has already responded to a barrage of
criticism over the last two years by quietly becoming more assertive
about keeping new drugs off the market or refusing to approve new uses
for existing medications.
The Nasdaq Biotechnology Index is down about 14 percent since late
February, in part on Wall Street’s perception that the F.D.A. has
become a tougher gatekeeper.
“The uproar that’s occurred in the wake of Vioxx has clearly had an
effect on the way the F.D.A. approaches its work,” said Ira Loss, who
follows the F.D.A. for Washington Analysis, a firm that monitors the
federal government for investors. “The agency doesn’t hesitate to say
‘No’ or ‘Send me more data.’ ”
Mr. Loss was referring to the market withdrawal of Merck’s painkiller
Vioxx for safety reasons two years ago. That episode ignited criticism
of the F.D.A. and prompted the agency to commission the report issued
last week by the federal advisory group, the Institute of Medicine.
Despite the report’s critique, executives and analysts point to
numerous unexpected delays and rejections by the F.D.A. since the
Vioxx debacle that they say show the agency is taking a tougher
stance.
Earlier this month, for instance, Genentech said approval of its colon
cancer drug Avastin as a treatment for breast cancer would be delayed
about a year because the F.D.A. had asked for more data. Genentech
said the agency appeared to be toughening its requirements for certain
types of clinical trials.
And some drugs that won approval in Europe have merely received
“approvable” letters from the F.D.A., meaning they will not be allowed
on the market without more information. These drugs include
Sanofi-Aventis’s Acomplia for obesity, NPS Pharmaceuticals’ Preos for
osteoporosis and Encysive Pharmaceuticals’ Thelin for pulmonary
hypertension.
Also whether from caution or a lack of manpower, it has also become
common for the agency simply to postpone decisions by 90 days. About
half a dozen drugs, including Pfizer’s inhaled insulin, Exubera, that
have been approved in the last several months were first subjected to
90-day delays.
The F.D.A.’s own statistics, too, show signs of a more cautious stance
— at least for new drugs that the agency does not consider major
advances over ones already available.
So far, only 1 of 14 such drugs submitted to the agency in the 2005
fiscal year — the Sucampo Pharmaceuticals drug Amitiza for
constipation — has won approval on the first try. That is the lowest
approval rate in at least a decade.
The main category in which the F.D.A. does not show signs of a
slowdown is in approval rates for new drugs that merit a priority
review, like the cancer drugs Sutent from Pfizer and Sprycel from
Bristol-Myers Squibb. Both were approved within a six-month review.
A reason for the seeming discrepancy between the perceptions of the
agency’s critics and the experience of the drug industry may be that,
to some extent, they are looking at different things. The Institute of
Medicine report, as well as bills in Congress aimed at reforming the
F.D.A., focus mainly on lapses in monitoring drugs already on the
market, not on the initial approval process.
Indeed, the Institute of Medicine report said the F.D.A. devoted too
much of its resources to reviewing new drug applications and not
enough to tracking post-approval safety. But the report also
criticized the approval process for emphasizing speed at the expense
of safety.
Dr. Bruce Psaty, a professor of medicine and epidemiology at the
University of Washington and one of the report’s authors, said that
given the time required to compile the report, it might not reflect
changes at the F.D.A. in the last few months.
It is difficult to judge whether the agency has actually become more
cautious, because the data on which it bases decisions are usually not
publicly released, and the agency does not discuss drugs under review.
That means much of the information about the F.D.A.’s actions come
from the drug companies themselves.
The F.D.A., which did not make anyone available to be interviewed for
this article, denies that there has been a change. So do some of its
critics.
The drug industry’s laments are “just major kvetching” said Dr. Sidney
Wolfe, the head of health research at the watchdog group Public
Citizen. He said that executives and Wall Street were looking for a
scapegoat for the pharmaceutical industry’s failure to develop better
drugs.
Even if there have been no official policy changes, though, people
close to the F.D.A. say the agency’s drug reviewers have become
worried they will be hauled before Congress if they approve a drug
that is later found to be unsafe. The lack of a permanent F.D.A.
commissioner for the last year, along with severe budgetary
constraints, are also cited as factors behind delays and rejections of
drug applications.
“I speak to reviewers, and they all feel very worried that the
decisions they make may come back to haunt them,” said Dr. Lee Simon,
a former F.D.A. division head, who is now an industry consultant.
One company that may have met such caution is Somaxon Pharmaceuticals
of San Diego. It is testing a tiny dose of doxepin, an antidepressant
that has been on the market since 1969, for use as a sleeping pill.
Jeff Raser, a co-founder and senior vice president for sales and
marketing, said that the F.D.A. had assured the company that it could
begin human clinical trials without first doing animal tests, because
of doxepin’s long history of use in people and because Somaxon was
using only about 1 to 8 percent of the dose used to treat depression.
But in May, after Somaxon had completed several clinical trials and
was meeting with the F.D.A. to discuss applying for approval, the
agency asked for a full battery of animal tests, Mr. Raser said. That
will delay the company’s application for at least six months.
Another F.D.A. tool, the “approvable” letter, has come to be seen by
some analysts as a way for the F.D.A. to make a decision by its
deadline but that is really a delaying tactic. The F.D.A. denies this.
In some cases there are just minor details to be worked out before
approval. But some analysts say the agency is increasingly asking for
more clinical trials, as in the case of Preos, NPS Pharmaceuticals’
osteoporosis drug.
Some F.D.A. delays have angered patient advocates, as with the request
for more data on Avastin, a Genentech cancer drug. They note that in a
clinical trial the drug, used in combination with the generic
chemotherapy treatment paclitaxel, delayed the worsening of breast
cancer by more than six months, compared with paclitaxel alone.
“This, as usual with the F.D.A., does not seem to be about whether the
drug combination works, or whether breast cancer patients would be
better off if they could get it,” said Steve Walker, chief adviser to
the Abigail Alliance for Better Access to Developmental Drugs, a
patient advocacy group.
The F.D.A. has also postponed by 90 days, until November, its deadline
for deciding whether to approve Genentech’s late-stage breast cancer
drug Herceptin for use in earlier stages of the disease.
And yet, the F.D.A. has recently approved drugs for serious diseases
in which few alternative medicines are available. In July, for
example, the agency approved Gemzar, from Eli Lilly, as a treatment
for recurrent ovarian cancer, even though its advisory committee had
recommended against approval — in part on grounds that the drug had
not prolonged survival, only delayed the worsening of cancer.Where a
new caution seems most evident is in the F.D.A.’s review of drugs that
may appear to provide few benefits over existing medicines.
One such case might be Sparlon, a drug for attention deficit disorder
developed by Cephalon. Sparlon is a higher-dose version of Provigil,
an alertness drug from Cephalon that was approved in 1998.
An F.D.A. advisory panel voted 12 to 1 in March that Sparlon’s safety
risks were too great to merit approval. Of particular concern was a
suspected case of Stevens-Johnson Syndrome, a rare but potentially
fatal blistering of the skin that can be caused by an allergic
reaction to a drug.
But the boy who supposedly had the syndrome was never hospitalized,
and Cephalon subsequently submitted evidence it said conclusively
showed that the boy had a different skin condition caused by a virus.
Even so, in August the F.D.A. rejected Sparlon.
“It’s amazing to all of us that a single case of a bad rash that the
experts have said is not Stevens-Johnson Syndrome would yield a result
from the F.D.A. of a nonapprovable letter,” Frank Baldino Jr.,
Cephalon’s chief executive, said in a conference call with analysts.
He said the company would drop the drug because approval hurdles were
too high.
Mr. Loss of Washington Analysis said Cephalon had not shown that
Sparlon was indispensable, given other drugs on the market. So even if
there were only a slight chance of a fatal side effect, he said, “why
would the F.D.A. take a risk like that?”
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