Jill Wechsler
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New leaders at the Food and Drug Administration are moving aggressively to address charges of incompetence and ineffectiveness
that have roiled the agency in recent years. The Government Accountability Office (GAO) added FDA to its High-Risk list of
government programs at the beginning of the year, largely due to inadequacies in drug oversight. GAO and other critics acknowledged
perceived shortfalls in government funding as a prime factor, along with the rising complexity of medical technology and increased
globalization of biomedical production.
To make FDA more efficient and competent, commissioner Margaret Hamburg has reorganized her executive office to emphasize
the importance of food safety and scientific integrity and to quickly inaugurate agency involvement in tobacco regulation.
Hamburg is broadcasting FDA's intent to aggressively enforce manufacturing and marketing rules and to vigorously implement
the multiple requirements established by the FDA Amendments Act of 2007 (FDAAA).
A sign of the activist tone at FDA is the steady flow of new regulations and policies. One set of new rules aims to expand
patient access to investigational medicines by finalizing several proposals long sought by patient advocates. The policy makes
it easier for seriously ill individuals to obtain unapproved drugs under the treatment IND policy or to have early access
to an approved drug for an unapproved indication. Sponsors gained important clarification on when they may charge patients
for an experimental drug outside a clinical trial.
Another recent proposal requires manufacturers to submit postmarket adverse event (AE) reports electronically. Leading pharma
companies already file 80 percent of individual case safety reports electronically under a pilot program testing FDA's Electronic
Submission Gateway. The new policy aims to make it easier for small biotech firms and medical device makers to follow suit
by establishing a new Web portal for agency-wide safety reporting as part of FDA's MedWatch Plus initiative.
The e-filing rule makes few changes in the scope and timing of manufacturer AE reports and continues to utilize standards
for data elements and format established by the International Conference on Harmonization that have been adopted in Europe
and Japan. For these reasons, the agency anticipates minimal compliance costs for industry. FDA, however, will save $2.4 million
a year by eliminating the manual conversion of paper reports to electronic form. More important, though, will be speedier
access to critical safety information; FDA says that reviewers are able to obtain electronic safety submissions in two days,
compared to two weeks to get paper reports into the agency's Adverse Event Reporting System.
Drug safety officials also are developing guidance on conducting observational studies using large data bases, along with
policies for reducing confusion over the names of new drugs. There's even a hint that FDA may try to finalize a massive set
of safety reporting rules for drugs and biologics ("The Tome") after years on hold.
Struggling With Safety
More Studies "On Time"
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One prominent FDAAA goal was to compel manufacturers to launch and complete post-approval safety studies on time. There seems
to be progress in this area, according to FDA's annual report on the status of postapproval studies issued last month. FDA
should improve its tracking and review of these studies following an assessment of pending and completed postmarket obligations
by Booz Allen Hamilton [see sidebar].
Risk Evaluation and Mitigation Strategies (REMS) also are more visible, although most of these postapproval safety programs
require manufacturers only to issue MedGuides for pharmacists to hand patients filling new prescriptions. Only a few REMS
require more formal plans for communicating risks to health professionals or more extensive "elements to assure safe use,"
such as limited distribution programs.
The unstated tradeoff for more investment in postapproval drug safety monitoring is supposed to be a less conservative agency
stance in approving new drugs for market. But the jury is still out on whether FDA reviewers have confidence that these postmarketing
initiatives will deflect outside criticism and calm internal dissent. The agency appears to be approving more new molecular
entities (NMEs), but taking longer to do so, as many reviews go beyond the first review cycle time frame.
In fact, the U.S. may be falling behind Europe in approving innovative therapies for patients. At a meeting last month sponsored
by the Institute of Medicine (IOM) to evaluate post-FDAAA safety initiatives, Merck executive vice president Peter Hoenig
noted that first cycle approval trends are down and that user fee approval dates are "routinely missed" due to increased scrutiny
of safety issues. FDA is "clearly struggling" with postmarket safety demands, he said, suggesting that "drug lag" may be rearing
up once more as European regulators approve some new drugs for market faster than in the US.
John Jenkins, director of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER), responded that
it's unclear whether FDA reviewers have become more conservative in assessing new products. He sees no dramatic fall-off in
NME approvals, but admitted that a decision to establish a REMS late in the review process will rule out a quick approval.
It also takes time and resources to determine the scope and timing of postmarketing studies, Jenkins added. Instead of assessing
sponsor proposals for the scope and schedule of safety studies, FDA now has to set the time lines and research parameters,
some thing that is very difficult for reviewers to calculate, Jenkins noted. Because some studies are likely to involve thousands
of patients, or more, CDER is planning to ask advisory committees to weigh in on acceptable postmarket study designs, number
of patients and end points. The aim is to obtain "public buy-in" that will help FDA deal with second-guessing later on if
a study is delayed or changed, Jenkins commented. Of course, scheduling more advisory committee meetings may delay approvals
even more.
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