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FDA Proposes Change To CBE Supplement Rule
Proposed rule to codify long-standing policy stirs debate
By Gary C. Messplay, J.D., and Colleen Heisey, J.D., M.P.H.
On January 16, 2008, the U.S. Food and Drug Administration (FDA) announced a proposed rule to amend its regulations regarding changes to an approved new drug application (NDA), biologics license application (BLA), or medical device premarket approval (PMA) application. The position long held by FDA is that certain labeling changes may be made with a supplemental application before FDA review. As stated in the preamble, FDA is using the proposed rule to "clarify that such a supplemental application may be used to add or strengthen a contraindication, warning, precaution, or adverse reaction," but only if there is adequate evidence to establish a causal relationship with the drug, biologic, or device. The amendments are intended to reaffirm and codify the Agency's longstanding position regarding what changes to drug, biologic, or medical device labeling can be made before its review of the change. However, industry, public interest groups, and even members of Congress differ in their views regarding the extent to which the proposed rule merely reaffirms the rule for labeling changes prior to FDA review as currently implemented by the Agency.
The Regulations: Current and Proposed
For drug products, 21 C.F.R. § 314.70(c)(6)(iii) establishes that certain labeling changes related to an approved drug may be implemented upon receipt by FDA of a supplemental new drug application that includes the change. Similarly, for biologics, 21 C.F.R. § 601.12(f)(2), describes that products with certain labeling changes may be distributed before FDA approval. Finally, 21 C.F.R. § 814.39(d) sets forth that certain labeling changes may be effected upon submission of a PMA supplement prior to the sponsor's receipt of a written FDA order approving the supplement. The supplements described by these sections of the regulations are known as "changes being effected supplements" or more familiarly, "CBE supplements."
The CBE supplement procedure for making changes to labeling is intended to be a narrow exception to the general rule that labeling changes must first be approved by FDA. This exception exists in order to allow a manufacturer to quickly convey newly discovered safety information to the user.
The proposed rule would clarify these regulations to confirm that utilizing a CBE supplement is proper to change approved labeling in two situations: (1) to reflect newly acquired information and (2) to add or strengthen a contraindication, warning, precaution, or adverse reaction when there is sufficient evidence of a causal association with the drug, biologic, or medical device. Even under the proposed rule, FDA would maintain its authority to accept, reject, or request modifications to the proposed changes, as appropriate. FDA states in the preamble to the proposed rule that allowing sponsors to unilaterally amend the labeling for approved products without limitation would undermine the FDA approval process required by Congress. Indeed, permitting a sponsor to unilaterally rewrite the labeling following FDA-approval of a product and its associated labeling would disrupt the careful equilibrium of how the risks and benefits of the product should be communicated.
Newly Acquired Information
The proposed amendments will make explicit the requirement that CBE supplements be used only to make labeling changes prior to FDA approval when there is newly acquired safety information. According to the proposed rule, safety information would be considered newly acquired "if it consists
of data, analyses, or other information not previously been submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events of a different type or greater severity or frequency than previously included in submissions to FDA, or new analyses of previously submitted data (e.g., meta-analysis)." In sum, the newly acquired safety information must provide new information about the product. For example, FDA provides that "a risk that is different in type or severity than previously known risks" would qualify as newly acquired safety information.
Causal Association
Under the proposed amendments, newly acquired safety information could only be used as a basis for submitting a CBE supplement and changing a product's labeling when there is also "sufficient evidence of a causal association with the drug, biologic, or medical device." FDA is proposing to rely on existing regulations and guidance for determining whether a causal association exists. For drugs and biologics, FDA proposes to rely on the standard set forth in Section 201.57 to determine whether sufficient evidence of a causal association exists with a drug or biologic for purposes of using the limited CBE procedure. This section of the regulations provides the criteria utilized to determine when safety information is appropriate for inclusion in the labeling of an approved drug or biologic's labeling. Under these rules, a sponsor is required to update labeling to include a warning or precaution about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug even if the causal relationship may not be definitively established. For adverse events, the rule requires the labeling to include a listing of all adverse reactions reasonably associated with the use of a drug. To list a reaction, there must be some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event. Finally, with respect to contraindications, the section provides that labeling should include situations in which the drug should not be used because the risk of use clearly outweighs any possible therapeutic benefit and directs; sponsors should only include known hazards as contraindications and not theoretical possibilities.
Similarly, for medical devices, FDA has opined in a 1991 memorandum that device labeling should include a warning if there is reasonable evidence of an association of a serious hazard with the use of the device and that a causal relationship does not need to be proven to include a warning. Adverse reactions should be listed in device labeling if they are reasonably associated with the use of a device, while a contraindication is warranted only where the risk of use clearly outweighs any possible benefit, including only known hazards and not theoretical possibilities.
Response to the Proposed Rule
FDA does not anticipate that the proposed amendments will affect its current practices regarding the acceptance or rejection of labeling changes made via CBE supplements. While FDA believes that the proposed amendments to its regulations will not be substantive changes, other parties, including committees in Congress, see the change as contrary to public health interests.
Outspoken critics of the proposed rule, such as Public Citizen and Consumers Union, question the proposed parameters for "newly acquired information" and "causality" and the timing of the proposed changes, stating that "[t]he agency has failed to demonstrate a need for revising this regulation, nor has it been able to point to a single case in which lack of clarity over the CBE supplement requirements have interfered with the process of changing a drug's label or adversely affected public health."
Opponents decry the proposed rule as an attempt by the Agency to preempt state tort law and to shelter companies from product liability for failure to warn patients and healthcare providers of product-related dangers unless the manufacturer has sufficient evidence to demonstrate causality.
Representatives of several Congressional committees, notably the House Oversight Committee and the Senate Committee on Health, Education, Labor, and Pensions, view the proposed rule similarly. In a letter to FDA Commissioner Andrew C. von Eschenbach, the legislators suggest that the proposal "will serve only to deprive American consumers of critically important and timely information about the safety of their drugs and medical devices . . . to protect companies in the pharmaceutical and device industry from being held liable for marketing products they know are unsafe."
The Pharmaceutical Research and Manufacturers of America (PhRMA) laud the proposed rule stating that "there is a strong public health rationale for the proposed rule" and "the proposed rule is fully consistent with the structure and intent" of the Federal Food, Drug, and Cosmetic Act. Moreover, PhRMA believes the proposed rule serves to update the regulations to reflect statutory and regulatory changes made since the regulation was first promulgated more than 20 years ago.
AdvaMed, The Advanced Medical Technology Association, however, has disagreed with the scope of the proposed rule on behalf of its member manufacturers of medical devices, diagnostic products, and medical information systems. In general, AdvaMed disagrees with excluding all previously submitted data from the definition of "newly acquired" as overly broad and potentially implicating information submitted in periodic reports, medical device reports, annual reports, or even investigational device exemption reports. AdvaMed agrees the CBE procedure should not be used to revisit previous PMA decisions, but that determining what information is considered "newly acquired" is problematic, suggesting that the Agency clarify the definition to include "the new understanding of information available in part at the time of review due to additional data which has come to light."
It is clear from the comments submitted regarding the proposed rule that stakeholders view the change as more than a simple codification of existing guidance or Agency policy.
