Bruce Mirken
Most Americans have no direct contact with the U.S. Food and Drug
Administration (FDA), but their lives literally depend on the effectiveness
of this agency. Charged with assuring the safety of specific foods and
all medicines, the FDA has oversight over a staggering 25% of the U.S.
economy.
One of the FDA’s key functions is approving and monitoring prescription
drugs—a job that is particularly crucial for people battling HIV infection
or other life-threatening diseases. During the 1980s, AIDS  activists
came to regard the FDA as a sort of tar pit into which promising new
drugs disappeared, seemingly stuck in a bureaucratic morass where dotting
every I and crossing every T took precedence over the urgent needs of
the sick and dying.
That overly simplistic view has changed substantially, but new questions
have arisen. In the late 1990s serious, long-term complications of antiretroviral
therapy began to emerge, while at the same time a rash of non-HIV-related
drugs (like the diet pill commonly called "fen-phen") were removed from
the market due to safety concerns that only became apparent months or
years after the drugs were approved. Many experts believe that at least
some of these problems could have been prevented by more aggressive
FDA monitoring of drugs after approval.
The Basics of Drug Approval
A pharmaceutical company or
researcher wishing to test an experimental drug must file what is known
as an Investigational New Drug (IND) application with the FDA. Technically,
the IND is a request for an exemption from the federal law that bans
any unapproved drug from being shipped in interstate commerce. Without
this exemption an unapproved drug cannot be sent across state lines,
making research impractical if not impossible.
The IND application, based on the drug’s preclinical development,
is intended to show that the drug is likely to be safe and that it has
pharmacological activity that justifies human testing. It generally
includes information about the drug’s molecular structure and how it
is manufactured as well as data from test-tube and animal studies. Animal
tests are used to develop a basic understanding of how the drug behaves
in a living system, such as how fast it is absorbed, metabolized, and
excreted. A key issue, of course, is toxicity, and the IND application
generally requires toxicity data from at least two animal species. The
IND also includes detailed protocols for the proposed clinical studies.
If the FDA determines that the drug is safe enough to proceed to
human testing, the IND is granted and Phase I trials can begin. Because
these studies represent the first human experience with a new drug,
they start quite cautiously. Phase I trials are generally small (usually
involving between 20 and 100 volunteers) and short-term, designed primarily
to see if the drug is safe.
Phase I studies usually enroll healthy volunteers. They are commonly
designed as dose-escalation or dose-ranging studies, in which researchers
start with very low doses and gradually work up to higher doses in succeeding
groups of participants, in an effort to determine what doses can be
given safely. Phase I studies also look at a drug’s pharmacokinetics,
which includes evaluating the levels the drug reaches in human blood
and tissues and how rapidly it is eliminated.
The FDA estimates that about 70 out of every 100 drugs pass Phase
I and go on to Phase II studies. These are the first trials that look
at a drug’s (or vaccine’s) efficacy—that is, whether the product does
what it was intended to do. Phase II studies are larger and longer than
Phase I studies, and they also generate important safety information.
If Phase II is successful, the product will go on to large Phase III
trials, which are designed to give enough proof of efficacy to allow
the FDA to approve it for sale. Researchers will occasionally attempt
to speed the process by designing studies that aim to accomplish the
work of two phases at once, e.g., a Phase I/II trial.
If Phase III trials are successful, the drug’s sponsor then files
a New Drug Application (NDA), the official request that the FDA approve
the drug for sale. This lengthy document, containing detailed information
from the studies done on the drug, is evaluated by the appropriate FDA
division. Anti-HIV drugs, for example, are evaluated by the Division
of Antiviral Drug Products. Drugs that treat AIDS-associated symptoms
or opportunistic diseases may be evaluated by another division, as appropriate.
Many, but not all, NDAs are reviewed by an advisory committee—a
group of  experts
selected by each FDA division to advise it on drug approval and other
issues. In the antiviral drugs division, explains acting deputy division
director Jeff Murray, MD, the advisory committee’s opinion is sought
when a drug being considered is the first in a new class (such as protease
inhibitors [PIs]), or when the data raise questions or uncertainty.
Convening the committee "adds about another month" to a review process
that in ideal circumstances can be completed in three months or less.
Approval, Traditional and Accelerated
Traditionally, a drug had to
show clinical benefit (i.e., it had to reduce deaths or illness) to
be approved. The manufacturer had to provide at least 48 weeks’ worth
of data based on clinical endpoints such as disease progression or death.
In a chronic, slowly progressive disease like AIDS, that meant Phase
III trials in the early years of the epidemic often needed to be large,
long, and slow as researchers tallied clinical endpoints: usually the
incidence (new numbers) of deaths and opportunistic infections (OIs).
Meanwhile, evidence was accumulating that surrogate markers—blood tests
such as CD4 cell counts and HIV RNA (viral load) levels—correlated strongly
with clinical benefit.
In the late 1980s, with no truly effective anti-HIV treatments
available and the AIDS death rate rising, the HIV-affected community
clamored for faster access to promising experimental drugs. The FDA
responded with two important changes. The first was called parallel
track, also known as expanded access, which was adopted in 1989 to allow
anti-HIV drugs that had passed  Phase
II to be provided free of charge to people who lacked viable alternatives
among approved drugs. Data collected from expanded access programs could
be used to supplement the data from Phase III trials in a drug’s NDA
package. Every anti-HIV drug approved since then has had some sort of
expanded access program during its final stages of development.
In 1991—again under community pressure—the FDA instituted accelerated
approval for drugs used to treat "serious or life-threatening conditions."
Accelerated approval refers to conditional or interim drug approval
granted on the basis of surrogate marker data, on the condition that
the drug company will complete traditional clinical endpoint studies
within a given length of time and submit them to the FDA. If the follow-up
studies are not conducted, or if their results are negative, the FDA
may order the drug be withdrawn from the market.
The nucleoside analog (NRTI) drugs ddI (Videx) and ddC (Hivid)
were the first medications to be granted accelerated approval, in 1991.
Regulations formalizing accelerated approval procedures took effect
in January 1993.
CD4 cell count was the first surrogate marker used to approve anti-HIV
drugs, but in the mid-1990s it was overshadowed by use of viral load
as a surrogate marker. Viral load is a much more direct measure of a
drug’s effect on HIV. Two of the first three PIs, saquinavir (Invirase
formulation) and indinavir (Crixivan), received accelerated approval
based on viral load data. (The third, ritonavir [Norvir], received full
approval.)
During this period, proof that viral load correlated closely with
an HIV positive person’s clinical prognosis quickly accumulated. In
July 1997 that data led to a significant change in anti-HIV drug approval.
As Dr. Murray explained to the Antiviral Drugs Advisory Committee a
year later, the FDA concluded that "measures of viral load...[are] a
suitable endpoint for both accelerated and traditional approval." A
drug could now get traditional approval based on its impact on viral
load, while "clinical endpoint studies should remain an option and may
be preferred [in] certain situations."
Acceptance of laboratory values rather than deaths or physical
symptoms as an endpoint was not unprecedented, as Dr. Murray noted.
"We approve drugs to lower cholesterol based on following cholesterol
[rather than waiting to see an impact on survival] and use glucose as
an endpoint for looking at antihyperglycemics. So this is certainly
nothing new."
Currently, even for anti-HIV drugs, at least 48 weeks’ worth of
data showing suppression of viral load are required for traditional
approval. Drugs still can receive accelerated approval based on shorter-term
data, usually 24 weeks.
Phase IV: Postmarketing
With accelerated approval,
postmarketing studies are required to demonstrate either clinical benefit
or long-term viral suppression. But even for drugs that receive traditional
approval there are frequently important questions that are not answered
in the preapproval studies. For example, there may be specific populations
that were not well represented in the initial studies, or there may
be unresolved questions about possible interactions with other drugs.
For this reason the FDA commonly asks for additional research to be
done after approval, known as Phase IV research.
The circumstances involving approval of the most recent PI, Abbott
Laboratories’ lopinavir/ritonavir combination marketed as Kaletra, illustrate
both types of postmarketing commitments (i.e., those involved with both
accelerated and traditional tracks). The drug received accelerated approval
on September 15, 2000, based primarily on one large Phase III trial
showing an impact on viral load and CD4 cell levels, supplemented by
data from smaller trials. Abbott is required to submit final data from
two ongoing Phase III trials to support traditional approval.
In addition, the FDA has asked for—and Abbott has agreed to provide—a
great deal of other research. This includes a number of analyses aimed
at determining Kaletra’s resistance profile and possible cross-resistance
with other drugs, plus studies to determine appropriate dosing when
it is used in combination with other PIs or with non-nucleoside reverse
transcriptase inhibitors (NNRTIs).
The approval letter for Kaletra lists projected submission dates
for these Phase IV data. Such dates are not established by law or regulation,
explains Lindsay Cobbs, Regulatory Operations Officer for Postmarketing
Studies in the FDA’s Center for Drug Evaluation and Research. The time
frames are established on a case-by-case basis and vary depending on
the nature of the studies required.
What if the company does not perform the additional, postapproval
studies it has agreed to do? The consequences depend on the type of
study. If the traditional approval requirements are not met for a drug
that has been granted accelerated approval, the FDA has the power to
take the drug off the market.
But the FDA has no such weapon with regard to postmarketing commitments
not tied to accelerated approval. "There’s not much regulatory teeth
to Phase IV commitments," Dr. Murray says. "It’s really just a good-faith
commitment." Still, because drug companies want to maintain a good relationship
with the FDA, he adds, "a lot of them get done."
Amazingly, there is no simple way for the public to find out what
Phase IV studies have been agreed to or whether they have been done
as promised. Though the FDA’s Web site (www.fda.gov) contains a mass
of information, data from the central database that the agency uses
to track Phase IV commitments are not included. When BETA asked
for the status of Phase IV studies on approved anti-HIV drugs, Dr. Murray,
Cobbs, and an FDA press spokesperson all gave the same answer: the only
way to obtain this information is to file a written request under the
Freedom of Information Act (FOIA). The FDA’s FOIA staff will evaluate
the request and decide what is releasable—and they can charge for the
labor and duplicating costs. BETA has filed such a request and
was informed that a prohibitive fee of $1,782 was first required.
The good news is that this unwieldy procedure is set to change
shortly, thanks to the FDA Modernization Act (FDAMA), passed by Congress
in 1997. This controversial law, designed primarily to speed the evaluation
and approval of new drugs, includes a provision requiring the FDA to
make an annual report to Congress on the status of Phase IV studies
and to make significant information available to the public.
The regulations formalizing these procedures were finalized this
past October and were scheduled to take effect in February. However,
implementation was pushed back to April when the incoming Bush administration
put a 60-day hold on all new regulations. Significant information on
the status of Phase IV studies that is not now readily available, including
rates of patient accrual, will be available on the FDA’s Web site and
reported to Congress. The FDA agreed to the pharmaceutical industry’s
request that certain information it considers proprietary, including
the actual Phase IV study protocols, not be made public.
That first report to Congress is due in October 2001, by which
time the FDA also hopes to have the information online, but Cobbs expects
those first reports to be incomplete. "There are literally thousands
of postmarketing commitments that we have to evaluate," he explains.
With the drug companies not required to start filing reports until late
April 2001, a full analysis may not be finished by the October deadline.
One of the issues the FDA is supposed to evaluate in its reports
to Congress is whether legislative action (for example, to strengthen
reporting requirements) is needed. Conceivably, if the report shows
that postmarketing commitments are not being met, it could spur a move
to give the agency new enforcement tools.
Safety Monitoring
One of the FDA’s most important
functions is to monitor the safety of drugs once they are on the market.
Drugs are typically tested on no more than a few thousand people, and
in the case of accelerated approval, the majority of them may have only
been followed for six months.
Clinical trial volunteers are studied "in a very controlled environment,"
adds Martin Himmel, MD, deputy director of the FDA’s Office of Postmarketing
Drug Risk Assessment. "It’s not really what happens in the real world."
Inevitably, toxicities will emerge that were not seen in the studies.
A problem—even a fatal one—that occurs on average in one out of every
one or two thousand persons may not be seen in clinical trials, or may
occur so rarely that a connection with the drug cannot be established.
Just as important, "drugs can have acute, short-term toxicities
and they can have slow, long-term toxicities," notes Stephen Fried,
author of the 1998 book Bitter Pills, a sharply critical examination
of the FDA’s drug safety program. People with HIV/AIDS learned about
drug toxicities the hard way, as conditions associated with body fat
and metabolic abnormalities emerged, turning the new term "lipodystrophy"
almost into a household word. "It was entirely predictable," Fried argues.
"These drugs weren’t tested for that long." Whether lipodystrophy was
truly foreseeable or not, more stringent preapproval testing or postmarketing
surveying might have allowed swifter assessment of this (or other) side
effects.
Fried is not against rapid approval of drugs to treat life-threatening
conditions, but he argues energetically that the FDA’s efforts to monitor
drug safety are not only underfunded and understaffed, but fundamentally
flawed by design. Fried notes that FDAMA loosened FDA control over the
 pharmaceutical
industry in important ways: it allowed drugs to be approved based on
only one well-controlled study instead of two, and it made it easier
for drug companies to tell physicians about off-label uses of drugs
(use of an FDA-approved drug for an indication other than that for which
it was approved). The act also extended a five-year-old program of industry
"user fees" paid to the FDA—fees that can be used only for drug
review and approval. Not a penny of this substantial pot of money can
go to monitoring the safety of approved drugs.
Fried is not the only one to argue that the balance between drug
approval and safety monitoring has been lost. In a May 1998 commentary
in the Journal of the American Medical Association (JAMA),
Thomas J. Moore, Bruce M. Psaty, MD, PhD, and Curt D. Furberg, MD, PhD,
noted, "While the FDA has more than 1,400 employees with principal duties
related to approving new drugs, a full-time staff of only 52 monitors
the safety of approximately 5,000 brand-name, generic, and over-the-counter
drugs already in the marketplace."
Dr. Himmel notes that the staff in his office has grown to 75—leaving
safety monitoring personnel outnumbered by those involved in approving
new drugs by a ratio of 19 to 1. MedWatch—the FDA office that gathers
and analyzes over a quarter million reports of drug-related adverse
events every year—makes do with a staff of four.
The JAMA piece echoed Fried’s central criticism of MedWatch:
as a passive system dependent on spontaneous reports from physicians
and drug companies rather than proactively surveying for problems, it
simply is not capable of protecting the public. Moore, Dr. Psaty, and
Dr. Furberg summed up the problem this way:
"It makes no more sense to monitor drug safety without knowing
the extent of serious injuries than to have a National Highway Transportation
Safety Administration operating without information about automobile
accidents, or a Federal Aviation Administration not knowing how many
airplane crashes have occurred."
The biggest problem with spontaneous reporting is that often it
does not happen. Physicians and pharmacists simply have too much else
to do, and reporting possible drug side effects frequently falls through
the cracks. In preparing a commentary for Postgraduate Medicine,
a trio of authors surveyed physicians and pharmacists, and reported
their results with horror. "None of the physicians we talked
with have ever reported a drug reaction, even though all of them
have seen serious reactions. Most physicians we talked to didn’t realize
the crucial role they could play in improving drug safety."
AIDS activists got a taste of MedWatch’s shortcomings during the
12th World AIDS Conference in 1998 in Geneva, at a meeting they called
to discuss the rapidly emerging constellation of lipodystrophic anomalies
associated with highly active antiretroviral therapy (HAART). Community
groups had amassed hundreds of reports of "protease paunch," facial
wasting, and other problems, while the FDA had only received several
dozen. The underreporting was likely aggravated by MedWatch’s definition
of "serious"—and thus reportable—adverse events, which seems to exclude
many of the early signs of lipodystrophy.
Other countries have more aggressive systems for monitoring drug
safety. France has a network of 30 regional "pharmacovigilance centers"
that actively look for drug problems. In Britain, during the first year
a drug is on the market, it comes with a postcard that consumers can
use to report side effects directly, and drug safety monitoring is kept
entirely separate from drug approval.
The JAMA authors suggested that the U.S. needs to consider
such an approach—a stronger and more independent approach than what
exists now. Fried went even farther in the afterword to the 1999 paperback
edition of his book, arguing for "a Legal Drug Czar...someone empowered
to be the public health conscience of the legal drug world. Someone
who can declare war against adverse drug reactions and enlist the support
of physicians, pharmaceutical companies, regulators, and pharmacists,
instead of pitting them all against each other."
Dr. Himmel counters that the FDA does not depend entirely on MedWatch.
"We have cooperative agreements to fill in the gaps." Under such arrangements
large providers such as HMOs furnish the FDA with information on drug
reactions that they have accumulated in their own databases. Dr. Himmel
argues that the system is reasonably good at doing what it is supposed
to do: generate a "signal" of potential problems that triggers further
investigation.
Still, he says, the agency is "looking into active surveillance
and the like, where we can prospectively monitor for certain problems.…
It’s something we’re actively looking at and talking to people about,
but right now it’s at its early stages."
In the meantime, people with HIV can take a proactive stance by
reporting their own drug reactions to their physicians, who have access
to MedWatch, the FDA’s reporting system. Consumers can also report serious
adverse reactions directly to the FDA by visiting www.fda.gov/opacom/backgrounders/problem.html,
or by calling MedWatch at 800-FDA-1088 (800-332-1088).
Bruce Mirken is a freelance writer based in San Francisco.
Selected Sources
Department of Health and Human Services, Food and Drug
Administration. Postmarketing studies for approved human drug and licensed
biological products; status reports, final rule. October 30, 2000.
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research. Regulatory
update from the division of antiviral drug products. July 14, 1998.
Fried, Stephen. Bitter Pills. Bantam, New York.
May 1999.
Griffin, Glen C. and others. Report every adverse drug
reaction! Postgraduate Medicine 101(4): 13–16. April 1997.
Kwitny, Jonathan. Acceptable Risks. Poseidon
Press, Crofton. 1992.
Moore, Thomas J. and others. Time to act on drug safety.
Journal of the American Medical Association 279(19): 1571–1573.
May 20, 1998.
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last updated 30 May 2001
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