In a letter to eight Congressional Democrats who claimed the proposed rule " has no purpose other than to shore up the industry's legal arguments for avoiding liability ", Stephen Mason, the FDA's acting assistant commissioner for legislation, insisted the proposals were " crafted in a way that, if finalised, would not inhibit appropriate and timely submissions of new safety information, or the Agency's ability to review supplements in a prompt manner ".
This would include an obligation to amend product labelling so that it included " a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug ".
Mason added.
A causal relationship with the product would not need to be established.
The objections to the proposed rule on Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologics, and Medical Devices centre on its relatively narrow definition of circumstances in which manufacturers may use CBE supplements to make labelling changes in advance of FDA review and approval.
The provision has been invoked by plaintiffs in product liability cases, who argue that failure to warn of potential new adverse effects through this procedure exposes manufacturers to tort liability under state law.
For their part, manufacturers typically contend that their ability to make unilateral labelling changes is strictly circumscribed, and that product liability claims based on a 'failure to warn' are pre-empted by FDA approval of the existing labelling.
The agency has also backed the pre-emption principle, both in the preamble to its January 2006 Final Rule on Requirements on the Content and Format of Labeling for Human Prescription Drug and Biological Products and in the proposed rule on CBE supplements issued in January.
Mason's letter shows that the number of CBE supplements filed with the FDA's Center for Drug Evaluation and Research (CDER) hit a peak of 626 last fiscal year since FY 2001, when CDER first started tracking the submissions electronically.
A total of 447 supplements were received by the CDER in FY 2006, 341 in FY 2005, 412 in FY 2004, 330 in FY 2003, 267 in FY 2002 and 288 in FY 2001.
Asked by Henry Waxman, Edward Kennedy, John Dingell and other Congressional Democrats why the FDA " believes that modifying the regulations has become a high public health priority at this time ", Mason denied there were any pervasive difficulties with the arrangements for CBE supplements as they stood.
"Although there are instances in which CBE supplements have been rejected by FDA, including for adding a warning that FDA believed unjustified, most CBE supplements are appropriate," he wrote.
" This is because sponsors have generally used the CBE supplements procedure in a manner consistent with the proposed rule and because FDA has encouraged sponsors to work co-operatively with the Agency in advance of submitting CBE supplements, and sponsors typically do so ."
Rather than seeking to address past misuse of the CBE supplement regulations, the proposed amendments were designed to " comport with the Agency's publicly stated long-standing policy regarding when CBE supplements are appropriate ", Mason added.
The initiative has drawn further flak from another group of Congressional Democrats including Representatives Bart Stupak, Lois Capps, Jan Schakowsky, John Barrow and Hilda Solis.
In a letter to Commissioner Andrew von Eschenbach, they asked the FDA to withdraw the proposed rule, saying it was " unclear why an agency that is clearly in crisis would seek to limit consumers' access to information about crucial health and safety risks ".
The FDA's " dire lack of resources " might account for the dramatic fall in enforcement actions undertaken by the agency in recent years, the letter suggested.
The number of warning letters issued by the FDA for violations of federal requirements had dropped by over 50 per cent from 1,154 in 2000 to 535 in 2005 (a 15-year low), it pointed out.
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Whatever the reason for this overwhelming lack of enforcement, it further illustrates the critical importance of requiring drug and medical device companies to update their warning labels, without prior FDA approval, at the earliest sign of potential hazards ," Stupak et al commented. "
The public cannot afford to wait for the FDA to act to enforce safety labelling requirements, given the FDA's recent failure to take appropriate enforcement actions. "
The FDA's critics also see the proposed labelling regulation as a breach of the " appropriate balance " Congress tried to achieve in the sweeping Food and Drug Amendments Act of 2007 (FDAAA) between " providing the FDA with the necessary authority to protect consumers from adverse drug events and preserving the ability of Americans to pursue common law remedies to hold drug manufacturers accountable for failing to warn consumers of dangerous drug side-effects ".
In fact, Stupak et al contended, the proposed rule " directly contradicts this language by reversing a drug manufacturer's obligation to warn of new risks and hazards and, instead, allowing these companies to claim immunity from liability because they had no duty to warn ".
The pharmaceutical industry disagrees.
In its comments on the FDA's proposed rule, Pharmaceutical Research and Manufacturers of America (PhRMA) argued that the proposals were backed up by the new FDAAA provision authorising the agency to mandate - on its own initiative - post-approval labelling changes based on significant new safety information.
As PhRMA noted, this provision included a 'Rule of Construction' stating: " This paragraph should not be construed to affect the responsibility of the responsible person or the holder of he approved application under section 505(j) to maintain its label in accordance with existing requirements …" .
In other words, the association claimed, the proposed rule " leaves in place a clearly defined regulatory pathway for the submission of CBE supplemental applications in accordance with the agency's longstanding policies on the scope and appropriate use of the CBE mechanism and in conformity with related changes in the statute and regulations that have taken place since 1985 ".
PhRMA advanced a number of arguments in support of the relatively narrow parameters for filing CBE supplements set out in the proposed rule.
Among these was the basic tenet of the Food, Drug & Cosmetic Act that only products pre-approved by the FDA - which included labelling - could be introduced into interstate commerce.
" Indeed, there is no CBE mechanism in the state for making changes to an approved product or labelling ," the association commented.
" The CBE was initiated as, and remains, an exercise of FDA's enforcement discretion to tolerate limited deviations from this Congressional mandate in circumstances where the public health favours immediate dissemination of the proposed change through labelling and where newly acquired information gives a manufacturer scientifically adequate grounds for a supplemental application proposing a safety-related labelling change ."
Like the FDA, PhRMA also invoked a public health rationale for not drawing the boundaries of CBE supplements too broadly.
If a products labelling were changed without " careful evaluation of relevant scientific evidence by drug safety experts, it will lead to confusion and undermine the fundamental public health purpose and utility of the labelling ", the association argued.
In the meantime, advocates of FDA pre-emption in state product liability cases have seen their hand strengthened by the US Supreme Court's 20 February decision in Riegel v. Medtronic .
This involved a lawsuit against Medtronic over a catheter - a Class III medical device pre-approved by the FDA - that had ruptured in the plaintiff's coronary artery during surgery.
Charles Riegel and his wife alleged that the Medtronic catheter was designed, labelled and manufactured in a manner that violated New York common law.
However, the Supreme Court ruled that the pre-emption clause in the Medical Device Amendments of 1976 barred common-law claims challenging the safety or effectiveness of a medical device marketed in a form that had been pre-approved by the FDA.
While this will bring some relief to manufacturers, their lawyers and the FDA, there is already talk of a swift Congressional response, with Representative Henry Waxman promising that " we'll pass legislation as quickly as possible to fix this nonsensical situation ".