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The 505(b)(2) new drug application (NDA) provides a potentially streamlined path for sponsors who have developed improvements to drug products that have previously received FDA approval.
The 505(b)(2) new drug application (NDA) provides a potentially streamlined path for sponsors who have developed improvements to drug products that have previously received FDA approval. Successfully navigating the process requires close communication with the FDA, but, for those who do so the potential benefits can be significant.
The 505(b)(2) process was established at the same time that Congress created the generic drug industry with passage of the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) in 1984. This legislation included section 505(b)(2) to encourage further innovation for drugs that have already received FDA approval. Specifically, this section permits submission of a new drug application containing one or more investigations necessary to approval that were not conducted by the applicant and for which the applicant has no right of reference. Innovations that may qualify for 505(b)(2) treatment include modifications to: dosage form, formulation, strength, route of administration, dosing regimen, indication for use, active ingredient and others. What makes this section unique is that it opens up the door to data leveraging, which may include both non-clinical and clinical studies as well as a resource that is often overlooked: the published scientific literature. And, unlike the case with generic drugs, section 505(b)(2) also provides for potential approval exclusivity of three to five years if clinical trial data is a requirement for approval. When a 505(b)(2) NDA qualifies for orphan drug designation, the award of exclusivity may be as much as seven years.
The 505(b)(2) Concept
The standard for approval of a 505(b)(2) NDA is the same as a traditional NDA. Both applications require inclusion of data demonstrating substantial evidence of safety and effectiveness. However, the source of the data is different. In a traditional NDA, you own all the data. In a 505(b)(2) NDA, you rely upon data that you don’t own or have a right of reference to, including published literature. For example, you can rely on general, non-product-specific published literature, the FDA’s previous finding of safety and effectiveness (i.e., previous NDA approval). In order to leverage this data, the 505(b)(2) sponsor needs to build a bridge back to the approved product, which may require bioavailability, bioequivalence or efficacy trials, for example.
Sponsors can begin to navigate the 505(b)(2) process by researching available FDA guidance’s and performing a thorough literature search on the active ingredient. The FDA has assembled a wealth of reference tools for sponsors to help them navigate the 505(b)(2) process. The most relevant of these FDA guidance’s are:
Applications Covered by Section 505(b)(2). This guidance, issued October 1999, describes the type of information that can be relied upon from a reference listed drug and what can and can’t be submitted in a 505(b)(2) application.
Listed Drugs, 30-Month Stays and Approval of ANDAs and 505(b)(2) Applications Under Hatch-Waxman, as Amended by the Medicare Prescription Drug, Improvement and Modernization Act of 2003, Questions and Answers. This guidance, issued October 2004, defines the concept of a listed drug as it applies to follow on NDAs, both ANDAs and 505(b)(2)s.
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. This guidance, issued January 2013, describes the substance and format of the data submission requirements for traditional NDAs, ANDAs and 505(b)(2) applications.
Formal Meetings Between the FDA and Sponsors or Applicants. This guidance, issued May 2009, provides basic information for requesting and conducting meetings with the FDA to seek its input on product development plans.
Getting Started: The Pre-IND Meeting
Establishing a dialogue with the FDA is critical to the success of any 505(b)(2) development plan. Typically, in a mere 10 weeks’ time, a sponsor can schedule a meeting with the relevant FDA review division, compile the necessary briefing information, hold the meeting and reach agreement with the FDA on the development objectives for its product. In just a short time, sponsors can build the necessary foundation to ensure a successful development pathway. But it all starts with a discussion with the FDA.
First and most important is the need to confirm that 505(b)(2) is a suitable path. The FDA can and will refuse to file an NDA for a drug that is a duplicate and therefore eligible for approval as an ANDA (505(j)). During pre-IND discussions, sponsors can also establish the product’s value and define the target label. Having the FDA’s buy-in to the proposed development strategy or at least having the agency’s input into the plan can save time and money and significantly accelerate the development process.
Additionally, the FDA can provide valuable input on your plans to leverage data from the approved drug. The FDA’s guidance “Formal Meetings Between the FDA and Sponsors” provides an excellent road map for beginning the necessary dialogue with the FDA to streamline your development path. The data needed in a 505(b)(2) NDA can usually be limited to demonstrating the value of the particular innovation or variation of the already approved product. The data needed can range anywhere from a simple demonstration of bioequivalence to a full verification of clinical safety and efficacy. Additionally, an objective assessment of available data in respect to how this data supports proposed labeling claims is imperative.
Also by meeting with the FDA, any significant objections or data gaps can be identified and addressed, thereby facilitating development or making any early go/no-go decision much more apparent. Unfortunately, data gaps are sometimes not terribly obvious. Take, for example, a product improvement made to an “old” NDA — that is, one approved prior to the enactment of the GLP regulations. A 505(b)(2) applicant wanting to rely on such an “old” reference listed drug will likely be asked to fill even non-clinical data gaps if a complete line of GLP toxicology data is not available for reference from the precursor NDA. The FDA must apply today’s approval standard when approving a product modification in a 505(b)(2), and this may require backfilling data that was not required at the time of the original NDA approval.
While data leveraging should be considered an opportunity, it needs to be realistically balanced against any data gaps identified. It pays to be optimistic but optimism should be tempered with a realistic assessment of probability of success. Your meeting with the FDA should clarify your assessment.
The 505(b)(2) process offers quite a few potential advantages by providing a method to obtain FDA approval of your product sooner, with fewer costly studies and yet still with the possibility of an award of exclusivity. Likewise, there are quite a few potential pitfalls in the 505(b)(2) process. With careful planning and with early consultation with the FDA, sponsors can maximize their chances of success.
About the Author:
Brian Bollwage, JD, is vice president of global regulatory affairs for Theorem Clinical Services, a leading, global provider of comprehensive clinical research and development services. In a career spanning more than 30 years with almost all of it focused on regulatory affairs, Bollwage is a leading authority on regulatory law.
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