Two important facts about recent pre-market submissions to the FDA are worth noting: (1) Most combination products in the U.S. are reviewed primarily by FDA’s Center for Drug Evaluation and Research (CDER); (2) The number of approvals for combination products and 505(b)(2) products is on the rise. For example, 28 percent of NDA approvals for combination products in 2014 occurred via the “abbreviated” 505(b)(2) regulatory pathway.i,ii So, what is the 505(b)(2) pathway, and how can it save you time and money when developing a combination product?
By Angela Drew, Olu Aloba, and Ken Phelps, Camargo Pharmaceutical Services
A combination product is defined as a product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are produced as a single entity, co-packaged, or separately packaged, but only intended for use together (21 CFR §3.2[e]). Combination products are developed to enhance the safety and effectiveness of non-combination medical products, and have the potential to provide enhanced therapeutic advantages compared to single-component products. A recent increase in the number of drug/device combination products reflects the marketing advantages of providing patients with improved convenience and intelligent design features.
FDA received 310 original premarket applications for combination products in Fiscal Year 2014. Typically, one center at FDA is assigned primary review jurisdiction. Most applications are assigned to FDA’s Center for Drug Evaluation and Research (CDER) for primary review, and therefore the applications for approval are submitted as New Drug Applications (NDAs). Primary review jurisdiction was assigned to the Center for Devices and Radiological Health (CDRH) and the Center for Biological Evaluation and Research (CBER) in 36 percent and 14 percent of applications in FY 2014, respectively.i
How To Determine Primary Review Jurisdiction
Under section 503(g)(1) of the Food and Drug Act, assignment of a premarket submission for a combination product to a center with primary jurisdiction (a lead center) is based on a determination of the combination product’s primary mode of action (PMOA). A final rule defining the primary mode of action as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product” was codified in 21 CFR §3.4.
In many cases, determination of the primary review jurisdiction (CDER, CBER, or CDRH) can reasonably be made by the sponsor. In cases where the PMOA cannot be distinguished for a combination product, you can submit a request for designation (RFD) to the Office of Combination Products (OCP). A response from OCP is provided within 60 days. In assigning the agency center with primary jurisdiction, OCP will determine the PMOA (i.e., drug/biologic/device).
In situations where it is not possible to determine which mode of action provides the greatest contribution, OCP will assign primary jurisdiction to the center that regulates other combination products with similar safety and effectiveness profiles. If there are no similar products, OCP will assign the combination product to the center with expertise on the significant safety and effectiveness questions presented by the investigational combination product.
Although primary jurisdiction over the premarket review will be assigned to one center at FDA, other centers likely will be consulted during the application review. Further, the marketing application will need to establish the safety and efficacy for each component type and for the complete product.
The 505(b)(2) Regulatory Pathway
So what are the options for approval when CDER has primary review jurisdiction? If the drug has not previously been approved by the FDA, a complete portfolio of studies will be required for an NDA that will be submitted via the 505(b)(1) pathway. However, if the drug component of the combination product has already been approved, or if there is significant information available on its use, the product may be eligible for submission and approval via the 505(b)(2) pathway.
So what is the 505(b)(2) regulatory pathway and how can it benefit you? The United States Code of Federal Regulations and the FDA’s Guidance for Industry: Applications Covered by Section 505(b)(2) define a 505(b)(2) application as one for which one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant, and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted (21 U.S.C. 355(b)(2)). In a nutshell, this means existing information about the drug can be leveraged to reduce the size and/or scope of your nonclinical and/or clinical program.
Note that we are referring to publicly available data, such as literature or approved product labeling, rather than an authorization for FDA to access confidential information in a master file. The public information can be referenced as evidence for safety and efficacy of a drug via the 505(b)(2) approval pathway. This means data from sources other than your own studies can be provided in lieu of a full nonclinical and clinical program.
To do this, you must demonstrate how the leveraged data is appropriate and of a standard that is acceptable to FDA, as well as justify why studies normally required for approval can be omitted. Appropriateness involves providing a rationale for how the information is relevant, and establishing a “scientific bridge” between the existing information and your product. Preparing these justifications is among the many nuances of the 505(b)(2) pathway.
For example, if you want to rely on studies in the literature, you need to be aware of any differences between your product and the product in the literature, in terms of the drug formulation and study population. Often, published studies do not contain enough detailed data to demonstrate the safety and efficacy of the product to FDA standards. Similarly, there may be differences in the indication, dosage form, or dosage between an approved product and your product that may affect the way in which the information can be used. This is where experience with the 505(b)(2) pathway can save you time and money.
Completing a 505(b)(2) Application
Note: This section only refers to drug/device combinations. Biologic/device combinations are not approved via the 505(b)(2) pathway and drug/biologic products without a device component are outside the scope of this article.
The sections in a 505(b)(2) application are generally the same as those for a combination product containing a novel drug. The difference lies in introducing the leveraged information about a drug in the summary modules in sufficient detail. From a device perspective, much of the testing will need to be performed with the complete product (i.e., the device and drug). Therefore, some device-specific information will need to be included in several modules of the NDA.
In particular, the quality section (Module 3) of the NDA will likely need to include the quality manual, design history file, design controls, device specifications, and the manufacturing process, depending upon the device. Results of human factors studies will similarly be included in the appropriate sections.iii Note that CDER will likely request a consultative review of Module 3 and other relevant modules of the NDA by CDRH.
The plan to develop a combination product for marketing approval should be mapped out as early as possible and shared with FDA for feedback. This could be done at a pre-IND or pre-submission meeting, depending on the center with primary review jurisdiction. Obtaining early feedback on the general plan is important in estimating the scope, cost, and timing of potential product approval, clearance, or licensure.
Given the unique safety and efficacy concerns surrounding most combination products, it is essential to ensure that FDA agrees at an early stage with the planned clinical and nonclinical testing, and that from the outset FDA is aware of the general scope of the entire program. If FDA does not agree, there can be major implications for cost and time that you and your investors don’t want to discover later in the process.
Early feedback will also give FDA a chance to let you know if they agree with your assessment of the center with primary review jurisdiction. Of course, unless a formal RFD has been submitted and assessed, the choice of review center is not binding, but you may get an idea of how FDA will view your product.
It also is a good idea to outline your proposed studies/plans to fulfill your requirements under the Pediatric Research Equity Act (PREA), as any preliminary feedback may reduce the number of review cycles of your Pediatric Study Plan. The general plan to develop any product should be considered dynamic, and should be discussed with FDA at each milestone meeting.
When developing a regulatory strategy, you should consider the requirements for each component of the product, as well as the entire product. Of course, the manufacturer’s quality management system (QMS) will need to reflect the requirements of both the drug and device components. This will be the topic of a future article.
The target product profile should be established early in the process and should cover both drug and device. Due to the uniqueness of most combination products, the entire product may need to be tested for attributes such as biocompatibility, stability (together and/or separate), and human factors usability, along with assessments of the effect of any design, formulation or process changes on the pharmacokinetics, indication, dosage form, dosage, etc. This will greatly depend on the type of product being developed, and requires careful consideration of the clinical and pharmaceutical quality issues arising for the specific product.
Examples of the considerations that may arise for combination products are provided in the Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products.
As with any development program, early consultation with FDA is strongly encouraged. Having FDA as a partner throughout the product development process makes good business sense.
About the Authors
Angela Drew, Ph.D., is a product ideation consultant at Camargo with expertise in 505(b)(2) drug development and approvals. Angela has worked in the pharmaceutical industry performing client product feasibility and due diligence assessments, Pre-IND and milestone meetings with FDA and IND and NDA submissions, including combination products. She is also experienced in preparing medical device submissions for FDA. Her current focus is product ideation for clients seeking to develop innovative products that benefit from the 505(b)(2) pathway.
Olu Aloba, Ph.D., RAC is Senior Director of Pharmaceutics at Camargo and serves as senior technical advisor on drug/device initiatives. Olu has more than 20 years of experience in pharmaceutical research and development, technology transfer, and regulatory submissions. He is a subject matter expert for various types of dosage forms, with expertise in quality-by-design (QbD) formulation and process development, analytical development, and development strategy. He also has earned the Regulatory Affairs Certification (RAC) professional credential through the Regulatory Affairs Professional Society.
Kenneth V. Phelps, President and CEO, applied more than three decades of industry drug development experience to found Camargo Pharmaceutical Services in 2003. As the industry authority on the 505(b)(2) regulatory approval pathway, Phelps leads the Camargo team that now has the largest percentage of 505(b)(2) submissions of any team submitting to the U.S. FDA. Phelps hosts seminars for U.S. and global companies on how to realize the opportunities of 505(b)(2) and expanded marketability. Phelps is also a founding member of the 505(b)(2) Forum, an assembly of product developers and service providers interested in improving best practices across the 505(b)(2) development process. Ken’s published articles, interviews, podcasts, and 505(b)(2) blog can be followed at blog.camargopharma.com