FDA Issues Its First Postmarketing Safety Reporting Regulations for Combination Products

The Food and Drug Administration (FDA) recently published a final rule setting forth the first postmarketing safety reporting regulations for combination products that have received FDA marketing authorization. Postmarketing Safety Reporting for Combination Products, 81(244) Fed. Reg. 92603-92626 (Dec. 20, 2016) (to be codified at 21 C.F.R. pt. 4) ("Final Rule"); see also 21 C.F.R. § 3.2(e) (defining "combination product" as, inter alia, a product comprised of two or more regulated components). The rule has an effective date of January 19, 2017, with some provisions requiring compliance on that date and others requiring compliance within eighteen months. Final Rule at 92603, 92619.

The new regulations are part of the FDA’s ongoing effort to ensure the consistency and appropriateness of the regulatory requirements for combination products. Id. at 92603. Previously, the FDA applied postmarketing safety reporting regulations from one or more of the combination product’s constituent parts. Id. at 92604. This led to inconsistent, incomplete, and duplicative reporting because the regulations for drugs, biological products, and devices differ from one another in their standards and timeframes. Id. The FDA intends the new regulations to ensure consistent, complete postmarketing safety reporting for combination products while avoiding duplicative reporting. Id. at 92604, 92606.

The new regulations do not constitute an entirely new reporting scheme for combination products, as proposed by some of the FDA’s stakeholders. Id. at 92605. Instead, the regulations explain which of the existing postmarketing safety reporting regulations apply to combination product applicants (entities holding an application for a combination product) and constituent part applicants (entities holding an application for a drug, biological product, or device as a constituent part of a combination product where the other parts’ applications are held by other entities). Id. at 92604; see also id. at 92624-25 (adding 21 C.F.R. §§ 4.100 and 4.101 to specify who is subject to the rule and to define certain terms).

Under the new regulations, combination product and constituent part applicants must comply with postmarketing safety reporting requirements corresponding to the type of application under which they received marketing authorization. Id. at 92604, 92605, 92607; see also id. at 92625 (adding 21 C.F.R. § 4.102(b)). Applicants who received authorization under a new drug application (NDA) or abbreviated new drug application (ANDA) must comply with the requirements described in 21 C.F.R. part 314. Id. at 92625 (adding 21 C.F.R. § 4.102(b)(2)). Applicants who received authorization under a biologics licensing application (BLA) must comply with the requirements described in 21 C.F.R. parts 600 and 606. Id. (adding 21 C.F.R. § 4.102(b)(3)). And applicants who received authorization under a premarket approval application (PMA) or other device application must comply with the requirements described in 21 C.F.R. parts 803 and 806. Id. (adding 21 C.F.R. § 4.102(b)(1)).

In addition, combination product applicants must submit specified reports based on the product’s constituent parts. Id. at 92604, 92606, 92607; see also id. at 92625-26 (adding 21 C.F.R. § 4.102(c)). The FDA is requiring these reports regardless of application type because they relate to particular characteristics and safety issues associated with the type of constituent part. Id. at 92606, 92608, 92614. For example, if the combination product contains a drug, the applicant must submit field alert reports regardless of application type. Id. at 92625-26 (adding 21 C.F.R. § 4.102(c)(2)). If the product contains a biological product, the applicant must submit biological product deviation reports. Id. at 92626 (adding 21 C.F.R. § 4.102(c)(3)). If the product contains a device, the applicant must submit five-day reports and malfunction reports, id. at 92625 (adding 21 C.F.R. § 4.102(c)(1)), and must summarize and analyze these reports in any NDA, ANDA, or BLA periodic safety update reports it submits under 21 C.F.R. § 314.80 or § 600.80, id. at 92608; see also id. at 92626 (adding 21 C.F.R. § 4.102(d)(1)).

The new regulations require constituent part applicants to share with the combination product’s other constituent part applicants within five days information about events involving death or serious injury and information about adverse experiences. Id. at 92604, 92608; see also id. at 92626 (adding 21 C.F.R. § 4.103(a)). The FDA reasons that this expedited sharing of information will ensure timely, complete reporting with regard to events that are brought to the attention of only one constituent part applicant. Id. at 92616. It notes that the regulations do not require the sharing of trade secret or confidential commercial information. Id. at 92617. Applicants are also not required to modify, organize, or evaluate the information before forwarding it to the other constituent part applicants. Id. Applicants must maintain records relating to the shared information, including the identity of the applicants with whom they shared the information and the date shared, for the longest retention period that applies. Id. at 92609; see also id. at 92626 (adding 21 C.F.R. §§ 4.103(b), 4.104(a)).

The regulations also specify which submission procedures and recordkeeping requirements applicants must follow. Id. at 92604, 92609; see also id. at 92626 (adding 21 C.F.R. §§ 4.104, 4.105). Constituent part applicants generally must comply with submission and recordkeeping requirements based on their application type. Id. at 92609; see also id. at 92626 (adding 21 C.F.R. §§ 4.104(a), 4.105(a)). Combination product applicants generally must comply with submission requirements based on the type of report they are submitting, and they must maintain records for the longest applicable period. Id. at 92609 (noting that both 21 C.F.R. part 314 (for drugs) and part 600 (for biological products) require recordkeeping for ten years); see also id. at 92626 (adding 21 C.F.R. §§ 4.104(b), 4.105(b)).

Readers are encouraged to refer to the Final Rule and the Code of Federal Regulations and to seek legal counsel as appropriate to determine how the new regulations might affect them. The FDA also indicates that it will publish guidance with further information on complying with the rule. Id. at 92609, 92612, 92617-19.