Although the bills limit the inclusion of distribution and use controls—requirements that could dictate precise parameters
for physician prescribing, pharmacy dispensing, and patient access—they also require companies to monitor, evaluate, and work
to improve the implementation of such controls. The House-bill REMS would permit companies to stop distribution of the drug
to physicians who fail to adhere to the REMS requirements. Since current risk-minimization programs already contain reasonable
efforts to monitor compliance, there is considerable concern among manufacturers that PDUFA IV may require companies to police
the use of their products and become more directly involved in physicians' practice of medicine. Physician groups have also
raised objections to the potential burdens of implementing multiple REMS at the patient level. Nonetheless, many believe that
the REMS approach is an inevitable compromise that is needed to put the drug safety debate on more rational footing. Indeed,
the implementation of similar measures is hardly "voluntary" in current drug sponsor–FDA negotiations, and many companies
are already complying with similar frameworks in other jurisdictions.
The House's bill would go further than the Senate's in authorizing FDA to require postapproval studies of drug risks. It would
also allow the agency to require companies to submit proposals for "marketing plans and practices for the drug," to ensure
that such plans do not undermine the REMS. While the FDA would not be authorized to make or direct changes, this provision
has been met with alarm by industry as an unprecedented step toward entangling the agency in highly proprietary business activities—and
an attempt to go beyond current postmarket enforcement focused on off-label promotion to actually dictating the terms of industry
Both bills lay out processes and timetables for review of REMS proposals as well as for resolution of sponsor–FDA REMS disputes,
with the Drug Safety Oversight Board tagged to give its OK. REMS would be reassessed on a periodic basis, potentially resulting
in the addition (or, likely more rarely, subtraction) of new REMS requirements. As for company submissions of REMS assessments,
the House bill would require them—at a minimum—for each of the first three years after approval, and then again at year seven.
The Senate bill, by contrast, would require reviews at the 18-month and three-year marks.
Such reassessments could become a critical element of postmarket drug safety. Although companies have long attended to drug
safety issues after approval, the REMS model would introduce a much more holistic and regularized approach. While the tools
in the REMS toolkit will become more refined and understood over time, the new framework will inevitably intensify the regulatory
burden on companies, not to mention healthcare practitioners and patients. Enforcement of the REMS provisions could include
civil penalties (with the House bill, $10 million for one violation and up to $50 million for continued violations, while
the Senate bill provides a maximum $2 million penalty for multiple violations).
4 Labeling Changes
At present, while companies can theoretically make certain safety-related labeling changes without prior FDA agreement—known
as the "changes being effected," or "CBE" regulation—as a practical matter, FDA ultimately controls the label. Most significant
label changes are the product of scientific exchange and negotiation over labeling language. The Senate bill would create
a new process for safety-related labeling changes, with specific timelines and mechanisms for dispute resolution and FDA action.
The House bill would go further, authorizing FDA to order safety-related labeling changes (based upon new safety information).
Congressional critics of FDA safety oversight have sought to minimize the potential impact of any such labeling-change process
on preemption of product-liability suits, in which plaintiffs have long sought to second-guess FDA labeling decisions by alleging
that the manufacturer could have implemented a labeling change under the "CBE" regulation. In fact, once a definitive, expedited
FDA safety-labeling-change process is in place, a "CBE" regulation does not make sense and will only thwart effective risk
communication. Thus, the best outcome would be a definitive science-based labeling-change regime that avoids both overemphasizing
a drug's dangers relative to its benefits and second-guessing FDA labeling decisions in product-liability litigation.