We’ve previously posted some summaries of the 21st Century Cures Act (Cures Act), which the President signed into law on December 13, 2016 (Public Law No. 114-255). (Those summaries are available here, here, and here.) This post focuses on only one section of the new law: Cures Act Section 3038, titled “Combination Product Innovation.” We did not cover Section 3038 in great detail in our prior summaries. Instead, given the significant changes made to the law and the potentially wide-ranging effects, we knew that a stand-alone post would be necessary.
Section 3038 spans roughly 15 pages of text and revises Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FDC Act) concerning the regulation of combination products. It has a number of interesting new features. Perhaps most striking is the importation of the FDC Act’s Hatch-Waxman provisions concerning drugs into the review of drug-device combination products.
1. Definition of PMOA
Section 3038 reaffirms FDA’s task of choosing a lead center (CDER, CBER, or CDRH) to regulate combination products based upon their “primary mode of action” (PMOA). The PMOA is “the single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.” FDA by regulation had already promulgated this definition of PMOA. Section 3038 incorporates the regulatory definition essentially unchanged into the statute.
Section 3038 also directs FDA to “conduct premarket review of any combination product under a single application, whenever appropriate.” This statutory provision is a nudge and not a change in existing law, because FDA already has this authority and often requires only a single application for a combination product. The “whenever appropriate” qualifier plainly continues FDA’s discretion to use separate applications in appropriate situations. 21 CFR 3.4(c).
2. Impact of Chemical Action
A new provision is the instruction to FDA that it “shall not determine” that the PMOA is “that of a drug or biological product solely because the combination product has any chemical action within or on the human body.” Under this new directive, the presence of chemical action is insufficient by itself for the Office of Combination Products (OCP) to find that the primary mode of action is that of a drug. It is left unexplained what additional evidence is required. Presumably, there would need to be evidence that the chemical action makes the greatest contribution to the therapeutic effects.
Absent such evidence, presumably the OCP would revert to the portion of the algorithm in its regulations applicable to cases in which it cannot be determined with “reasonable certainty” which mode of action makes the greatest contribution. 21 CFR 3.4(b). The algorithm requires the OCP to determine which center has regulated similar combination products or is best equipped to handle the relevant safety or effectiveness questions raised by the combination product.
If this interpretation is correct, Section 3038 seems likely to move the OCP away from more formalistic inquiry as to the presence (or absence) of chemical action and its putative role in achieving therapeutic effects, and toward a more practical inquiry as to which center is best suited to review a particular combination product. That would be an improvement.
A similar issue sometimes arises when the OCP must determine whether a single entity product is a drug or device. In practice, the OCP places the burden of proof on a sponsor to show that its product does not achieve its primary purposes via chemical action if any is present. If the sponsor cannot meet this often difficult evidentiary burden, the OCP will likely classify the product as a drug. Section 3038 does not address the regulation of single entity products.
3. Meetings and Studies
Once a combination product is assigned to a lead center, a sponsor who disagrees may require the OCP to provide a substantive rationale and scientific evidence underlying the decision. The provision also spells out a collaborative process by which a sponsor and the OCP are to reach agreement within 90 days on the design of proposed studies (preclinical, clinical, or both) to establish the relevance of chemical action in achieving the primary mode of action. The OCP is then required to reconsider its decision in light of the data from such studies.
It remains to be seen how useful this provision is. Conducting clinical studies simply to establish product jurisdiction (as opposed to demonstrating safety and efficacy) will add yet another costly burden to the approval process. On the other hand, some products will not survive inappropriate placement in CDER. If that occurs because of a lack of data about the role of chemical action, it may be worth trying to save them by conducting studies that would answer this question.
After a PMOA is determined, there is a new procedure for requesting a meeting with the OCP within 75 days to clarify and reach written agreement upon what standards and requirements for clearance or approval of the combination product will apply and what postmarket requirements relating to manufacturing and product modification will apply.
4. Hatch-Waxman Rules Apply for Certain Combination Products
Section 3038 addresses the thorny issue of combination products that incorporate an already approved constituent. For example, it is not uncommon for new devices to be invented that improve upon the delivery of approved drugs, or provide a new route of administration for otherwise approved drugs.
Under Section 3038, FDA is instructed that “[f]or purposes of conducting the premarket review of a combination product that contains an approved constituent part,” FDA “may require that the sponsor of [the] combination product submit . . . only data or information . . . necessary to meet the standard for clearance or approval, . . . including any incremental risks and benefits posed by such combination product, using a risk based approach and taking into account any prior finding of safety and effectiveness or substantial equivalence for the approved constituent.” As a general matter, this provision should relieve sponsors of the burden re proving the basic safety or effectiveness of the approved constituent. It allows focus on the new constituent plus the incremental risk created by a new use of the approved constituent.
But there’s a flip side to this benefit. If a combination product has a device primary mode of action (PMOA) and the other constituent is an approved drug, then Section 3038 essentially imports the familiar panapoly of Hatch Waxman requirements applicable to 505(b)(2) NDA applicants into the device clearance and approval processes. Here’s what new FDC Act § 503(g)(5) says:
(A) If an application is submitted under section 515 or 510(k) or a request is submitted under section 513(f)(2), consistent with any determination made under paragraph (1)(D), for a combination product containing as a constituent part an approved drug—
(i) the application or request shall include the certification or statement described in section 505(b)(2); and
(ii) the applicant or requester shall provide notice as described in section 505(b)(3).
(B) For purposes of this paragraph and paragraph (4), the term ‘approved drug’ means an active ingredient—
(i) that was in an application previously approved under section 505(c);
(ii) where such application is relied upon by the applicant submitting the application or request described in subparagraph (A);
(iii) for which full reports of investigations that have been made to show whether such drug is safe for use and whether such drug is effective in use were not conducted by or for the applicant submitting the application or request described in subparagraph (A); and
(C) The following provisions shall apply with respect to an application or request described in subparagraph (A) to the same extent and in the same manner as if such application or request were an application described in section 505(b)(2) that referenced the approved drug:
(i) Subparagraphs (A), (B), (C), and (D) of section 505(c)(3).
(ii) Clauses (ii), (iii), and (iv) of section 505(c)(3)(E).
(iii) Subsections (b) and (c) of section 505A.
(iv) Section 505E(a).
(v) Section 527(a).
To translate this statutory language: the sponsor of the combination product must submit a certification with respect to any patent information identified in the Orange Book for the listed drug identified, and, in the case of a Paragraph IV certification, provide notice that the challenged patent(s) is invalid, unenforceable, or not infringed. If the NDA holder or patent owner timely brings suit, then approval of the 510(k) or PMA for the proposed combination product can be delayed up to 30 months while patent infringement is litigation. After that, clearance or approval could be granted, but if patent infringement litigation is not finally resolved, then a combination product sponsor will need to decide whether or not to market its product “at risk.”
New FDC Act § 503(g)(5) also imports various exclusivity provisions into the device clearance and approval processes. Subsection (C) above says that 5-year new chemical entity exclusivity, 3-year new clinical investigation exclusivity, 6-month pediatric exclusivity, 7-year orphan drug exclusivity, and any 5-year add-on exclusivity as a result of the 2012 Generating Antibiotic Incentives Now Act apply to prevent use of the drug in the combination product.
It appears that the Hatch-Waxman provisions are triggered only if the combination product is reviewed under the device provisions of the FDC Act and there is an approved drug constituent. They can be avoided if separate marketing applications are submitted (one for the device and the other for the drug), and Section 3038 expressly provides that nothing prevents the sponsor for doing so, unless FDA determines that a single application is necessary.
These statutory changes clearly have an impact on combination products in which a device and drug are physically combined or are packaged together. In such cases, the sponsor can control the labeling and make it harmonious with the intended use of each constituent, and FDA’s premarket data requirements now must focus only on the unapproved device and the incremental risk of the combination product as a whole.
Section 3038 apparently does not address the thornier issue of combination products created by cross labeling. In such cases, a new device and an approved drug would be sold separately, and changes are needed for the drug labeling to make it compatible with the new device. Such products have been stymied by lack of cooperation from the drug sponsor. It does not seem that Section 3038 provides any relief from the necessity to obtain such cooperation. Section 3038 only provides a solution when the combination product sponsor is in full control of all relevant labeling.
Curiously, although Section 3038 incorporates Hatch-Waxman into the device approval/clearance process, the provision makes no mention of combination products containing a proposed device with a biological constituent already licensed under the Public Health Service Act. Will a future bill or amendment reference the 2009 Biologics Price Competition and Innovation Act and, in particular, the statute’s 12-year (and pediatric) exclusivity provisions and complex patent resolution process?