FDA Auto-Injector Citizen Petition Response Adds Greater Clarity to Drug/Device Combination Product Generic Drug “Sameness” Requirements – Clinical Usability is an Important Consideration

By Kurt R. Karst –      

FDA’s recent response denying and granting in part two citizen petitions submitted by King Pharmaceuticals, Inc. (“King”) to FDA in September 2007 and January 2009 provides helpful guidance for companies developing generic versions of drug products containing a device component, such as a pen, jet, or related injector device.  Among other things, the King petitions requested that FDA decline to approve (or stay the approval of) ANDAs that reference a drug product containing an auto-injector device component – and in particular ANDAs for a generic version of IMITREX (sumatriptan succinate) Injection – unless the auto-injector is “identical” to that in the Reference Listed Drug (“RLD”) in terms of performance, physical characteristics, and labeled instructions.  (A product consisting of drug and device components is considered a “combination product” under FDA’s regulations at 21 C.F.R. § 3.2(e).  In April 2009, FDA issued a draft guidance for industry and FDA staff providing recommendations on the submission of NDAs and BLAs for combination products with an auto-injector component.)

Prior to responding to the King petitions, FDA provided only minimal guidance on how similar the device component in a proposed generic drug must be to that of the RLD.  For example, FDA’s April 2003 “Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action” states that “[a]ssurance of equivalence on the basis of in vitro tests is greatest when the test product uses the same brand and model of devices . . . as used in the [RLD].”  In addition, in a February 13, 1996 response to citizen petitions (Docket No. 1994P-0139) submitted to FDA concerning generic albuterol, FDA noted that “the generic delivery device should be functionally equivalent to that of the [RLD].  Although the identical valve and actuator may not be available to the generic firm, the generic drug product incorporating the valve and actuator selected by the generic firm must be similar in its comparative in vitro tests, and result in a product that meets in vivo requirements for bioequivalence.” 

FDA’s response to the King petitions notes that when reviewing an ANDA for a generic version of a combination product with an auto-injector component, the Agency evaluates the auto-injector component “to ensure that its performance characteristics and critical design attributes will result in a product that will perform the same as the RLD.”   FDA clarifies, however, that “[t]his does not mean . . . that all design features of the auto-injector in the ANDA and its RLD must be exactly the same.”  Instead, “[s]ome design differences may be acceptable as long as they do not significantly alter product performance or operating principles and do not result in impermissible differences in labeling.”  FDA further notes that:  

ANDA applicants . . . would be required to provide details on attributes such as auto-injector design, materials, operating principles, and comparative performance tests between the auto-injector constituent of the RLD and the auto-injector constituent of the product described in the ANDA.  If FDA determines that the auto-injector constituent of a product proposed in an ANDA is not equivalent to the auto-injector constituent of the RLD in terms of performance and critical design, FDA will refuse to approve the ANDA for that product.  Similarly, if the labeling is not the same (with the exception of certain pennissible differences due to difference in manufacturer), ANDA approval will be denied.

Importantly, FDA’s petition response highlights the concept of “clinical usability” as a critical factor in assessing product “sameness,” and that could foreclose the ANDA approval route.  FDA states:

For ANDAs for a product with labeling that describes use by patients without physician supervision and further requires training of patients by a physician prior to initial unsupervised use, FDA considers whether patients can be safely switched to a new product without retraining by a physician or health care professional.  For an ANDA for a product intended for emergency use by patients without professional supervision (such as a prefilled auto-injector indicated for emergency treatment of allergic reactions), it is particularly important to ensure that patients in an emergency situation can use the product safely and effectively in accordance with instructions provided for the RLD without additional physician intervention or retraining prior to use.  A similar standard may be applied to certain products not intended for emergency use, if appropriate. . . .

Clinical usability or human factor studies may also be required, depending on the indication and the patient population, the nature of the auto-injector design, and differences from the auto-injector constituent part of the RLD, to ensure that the proposed product is safe and effective.  If required, such studies are beyond the scope of studies that can be reviewed and approved in an ANDA. [(emphasis added)]

In the case of sumatriptan auto-injectors, we note that individuals experiencing migraines (the indication for which sumatriptan auto-injectors are indicated) may experience varying degrees of mental impainnent, and this may affect the usability of an autoinjector, leading to possible errors or misadministration ofthe product. . . .  [I]n reviewing an ANDA referencing this product, FDA will have to consider whether, given the characteristics of the proposed auto-injector constituent, the product can be safely substituted for the RLD without additional physician intervention or retraining prior to use.

Although FDA’s petition response is specific to combination products with an auto-injector component, it is reasonable to conclude that the Agency applies similar requirements and concepts when evaluating applications for generic versions of other device-containing combination products.  As such, companies would be well advised to seek FDA’s input when considering developing and seeking FDA approval for their combination products.